Neuroactive androgen receptor modulator and use thereof

Abstract

The present invention relates to a neuroactive androgen receptor modulator and the use thereof. The present invention relates to a novel arylpropionamide ester compound represented by formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, or isotopic derivative thereof, and relates to a pharmaceutical composition containing such a compound and to the use of such a compound and the pharmaceutical composition containing such a compound in the prevention and / or treatment of androgen-related diseases, in particular central nervous system diseases. The compound represented by formula I has good androgen receptor binding capability and androgen receptor modulating capability, and can pass through the blood-brain barrier, thus performing an androgen receptor modulating function in the brain.

Description

Neuroactive androgen receptor modulators and uses thereof Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology and relates to neuroactive androgen receptor modulators and their uses. Specifically, the present invention relates to novel arylpropionamide ester compounds or pharmaceutically acceptable salts, stereoisomers, solvates, or isotopic derivatives thereof, pharmaceutical compositions comprising such compounds, and the use of such compounds and pharmaceutical compositions comprising such compounds for preventing and / or treating androgen-related diseases, particularly central nervous system diseases. Background Art

[0002] The androgen receptor (AR) belongs to the nuclear receptor family and is a receptor for ligand-induced nuclear transcription factors. The androgen receptor is an important cellular regulatory protein that, through endogenous androgens, plays a crucial role in a range of physiological processes, including the development and maintenance of male secondary sexual characteristics, including muscle and bone mass, male hair growth, prostate growth, and sperm development. Endogenous steroidal androgens are known as male sex hormones and include testosterone and dihydrotestosterone (DHT). Testosterone is the primary steroidal androgen found in male serum and is primarily secreted by the testicles. In many peripheral tissues, such as the prostate and skin, testosterone can be converted to the more active androgen dihydrotestosterone (DHT) by 5-reductase.

[0003] Many diseases are linked to androgen levels. As men age, their androgen levels gradually decline, leading to muscle loss, osteoporosis, decreased sexual function, and cognitive decline. Conversely, excessive androgen levels can also lead to several diseases, including prostate cancer, benign prostatic hyperplasia (BPH), acne, hirsutism, and hair loss.

[0004] Testosterone and its active metabolite, dihydrotestosterone (DHT), play many important roles in the brain, including stimulating neuronal differentiation, maintaining neuronal morphology, increasing synaptic density, regulating neuronal viability, and protecting neurons. The androgenic effects of testosterone and other androgens are mediated by activation of the androgen receptor (AR). AR receptors are primarily found in multiple brain regions, including the amygdala and hippocampus, areas associated with learning and memory.

[0005] Androgens are believed to be related to many aspects of cognition, including language fluency and spatial cognitive ability. Excessively low androgen expression is often associated with cognitive impairment to a certain extent. Androgens are not only related to the cognitive level of older men, but also to the cognitive level of older women. Many studies have shown that as androgen levels decrease, many neurobehavioral factors related to them will be affected, and the risk of brain diseases will increase, especially the risk of AD. Traditional androgen therapy is effective in improving the above symptoms, but it has side effects such as inducing prostate cancer. In contrast, selective androgen receptor modulators (SARMs) have high specificity, few side effects, and more therapeutic advantages. However, there are currently no literature reports on the use of SARMs to treat central nervous system diseases, nor have there been reports that existing SRAMs can pass through the blood-brain barrier.

[0006] In recent years, aryl propionamide ester compounds have been found to be a class of selective androgen receptor modulators with excellent activity, and have made significant progress in the treatment of prostate cancer, breast cancer and other fields (see Ramesh, N. et al., Selective Androgen Receptor Modulators (SARMs) Negatively Regulate Triple-Negative Breast Cancer Growth and Epithelial: Mesenchymal Stem Cell Signaling, PLoS One, 2014.9(7):e103202). At present, aryl propionamide ester non-steroidal selective androgen receptor agonists such as Ostarine (also known as enobosarm, S-22, MK-2866 or GTx-024) and Andarine have been used in a number of clinical studies for different diseases (see Machek, SB et al., Considerations, Possible Contraindications, and Potential Mechanisms for Deleterious Effect in Recreational and Athletic Use of Selective Androgen Receptor Modulators (SARMs) in Lieu of Anabolic Androgenic Steroids: A Narrative Review, Steroids, 2020 (164): p. 108753), but there is no report that the above compounds can penetrate the blood-brain barrier (see Miner, JN et al., An Orally Active Selective Androgen Receptor Modulator Is Efficacious on Bone, Muscle, and Sex Function with Reduced Impact on Prostate.Endocrinology, 2007.148(1), pp. 363-373; Piu, F. et al., Pharmacological Characterization of AC-262536, A Novel Selective Androgen Receptor Modulator. The Journal of Steroid Biochemistry and Molecular Biology, 2008.109(1), pp. 129-137; Vajda, EG et al., Pharmacokinetics and Pharmacodynamics of LGD-3303[9-Chloro-2-Ethyl-1-Methyl-3-(2,2,2-Trifluoroethyl)-3H-Pyrrolo-[3,2-f]Quinolin-7(6H)-One], An Orally Available Nonsteroidal-Selective Androgen Receptor Modulator. J Pharmacol Exp Ther, 2009. 328(2), pp. 663-670). No SARM compounds have entered the clinic for central nervous system diseases. At the same time, there is also room for improvement in the androgen receptor agonist efficacy of the above compounds. Therefore, the development of neuroactive androgen receptor modulators (NARMs) that can penetrate the blood-brain barrier and have higher agonist efficacy can overcome the shortcomings of the above two types of treatments and is expected to become a new treatment strategy for central nervous system diseases targeting the androgen receptor.

[0007] Summary of the Invention

[0008] The present invention aims to provide a class of neuroactive androgen receptor modulator compounds (NARMs) that can penetrate the blood-brain barrier and have higher agonist efficacy. The inventors have completely transformed traditional aryl propionamide ester compounds through a series of modern drug development technologies, thereby obtaining a new class of aryl propionamide ester compounds. These compounds have higher agonist efficacy on androgen receptors, can effectively penetrate the blood-brain barrier, maintain a certain drug concentration in the brain, and exert androgen receptor regulatory function, thus better meeting the new needs of treating central nervous system diseases.

[0009] The first aspect of the present invention provides a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopic derivative thereof:

[0010] in

[0011] R1 and R2 are each independently cyano, halogen, halogenated C1-C6 alkyl, nitro or -NR5R6;

[0012] R3 and R4 are each independently hydrogen, cyano, halogen, halo C1-C6 alkyl, nitro, -NR5R6, -C(O)C1-C6 alkyl, -N(R7)C(O)C1-C6 alkyl, -N(R7)C(O)-halo C1-C6 alkyl, -C1-C6 alkyl C(O)C1-C6 alkyl, -S(O)2-C1-C6 alkyl, -N(R7)-S(O)2-C1-C6 alkyl, C1-C6 alkyl or C1-C6 alkoxy;

[0013] W is CH or N;

[0014] L is a bond, -C(O)-, -C(O)O-, -S(O)2-, or -C(O)NH-;

[0015] R is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 Aryl, 3 to 12 membered heterocyclyl, 3 to 12 membered heterocyclyl-C1-C6 alkyl, 5 to 12 membered heteroaryl, -C1-C6 alkyl-NRR6, glucosyl or amino acid, wherein the heterocyclyl and heteroaryl contain 1 or 2 heteroatoms independently selected from N, O or S, and the cycloalkyl, aryl, heterocyclyl and heteroaryl are optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, cyano; and

[0016] R5, R6 and R7 are each independently H or C1-C6 alkyl.

[0017] In some embodiments, the compound has the following Formula II:

[0018] wherein R1, R2, R3, R4 and W are as defined above for the compound of formula I.

[0019] In some embodiments, the compound has the following Formula III:

[0020] wherein R1, R2, R3, R4, W and R are as defined above for the compound of formula I, with the proviso that R is not hydrogen.

[0021] In some embodiments, the compound has the following Formula IV:

[0022] wherein R1, R2, R3, R4, W and R are as defined above for the compound of formula I, with the proviso that R is not hydrogen.

[0023] A second aspect of the present invention provides a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopic derivative thereof and one or more pharmaceutically acceptable carriers.

[0024] The third aspect of the present invention provides a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopic derivative thereof, or a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopic derivative thereof and one or more pharmaceutically acceptable carriers, which is used to prevent and / or treat androgen-related diseases, particularly central nervous system diseases.

[0025] A fourth aspect of the present invention provides a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopic derivative thereof, or a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopic derivative thereof and one or more pharmaceutically acceptable carriers for preventing and / or treating androgen-related diseases, particularly central nervous system diseases.

[0026] A fifth aspect of the present invention provides the use of a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopic derivative thereof, or a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopic derivative thereof and one or more pharmaceutically acceptable carriers in the preparation of a medicament for preventing and / or treating androgen-related diseases, particularly central nervous system diseases.

[0027] A sixth aspect of the present invention provides a method for preventing and / or treating androgen-related diseases, particularly central nervous system diseases, in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopic derivative thereof, or a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopic derivative thereof and one or more pharmaceutically acceptable carriers.

[0028] In the above aspects 3 to 6, the central nervous system disease is dementia (including Alzheimer's disease), cognitive deficits in schizophrenia, Parkinson's disease, Huntington's disease, depression, anxiety, stroke, cerebral ischemia, amyotrophic lateral sclerosis, traumatic brain injury, fragile X syndrome, Rett syndrome, brain tumor or obesity. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] FIG1 shows a curve showing changes in the concentration of the compound of Example 3 in mouse serum over time from 0 to 240 minutes after administration.

[0030] FIG2 shows a curve showing the concentration of the compound of Example 3 in the mouse brain over time from 0 to 240 minutes after administration.

[0031] FIG3 shows a curve comparison of the concentration changes of the compound of Example 3 in the mouse brain and serum over time from 0 to 240 minutes after administration.

[0032] FIG4 shows a curve showing changes in the concentration of the compound of Example 3 in mouse serum over time from 120 to 480 minutes after administration.

[0033] FIG5 shows a curve showing the concentration change of the compound of Example 3 in the mouse brain over time from 120 to 480 minutes after administration.

[0034] FIG6 shows a curve comparison of the concentration changes of the compound of Example 3 in the mouse brain and serum over time from 120 to 480 minutes after administration.

[0035] FIG7 shows a curve comparison of the concentration changes of the compound of Example 3 in the mouse brain and serum over time from 2 to 72 hours after administration.

[0036] FIG8 shows a curve comparison of the concentration changes of the compound of Example 8 in the mouse brain and serum over time from 12 to 72 hours after administration.

[0037] FIG9 shows a curve showing the concentration changes of the compound of Example 13 and its metabolites in mouse serum over time from 0 to 240 minutes after administration.

[0038] FIG10 shows a curve showing the concentration changes of the compound of Example 13 and its metabolites in the mouse brain over time from 0 to 240 minutes after administration.

[0039] FIG11 shows a curve comparison of the total concentration of the compound of Example 13 and its metabolites in the mouse brain and in the serum over time from 0 to 240 minutes after administration.

[0040] Figure 12 shows a curve comparison of the total concentration of the compound of Example 13 and its metabolites in the mouse brain and the total concentration in the serum from 0 to 240 minutes after administration, and the total concentration of the compound of Example 3 in the mouse brain and the total concentration in the serum over time.

[0041] FIG13 shows a curve showing the time-dependent changes in the concentration of the compound of Example 13 and its metabolites in mouse serum from 120 to 480 minutes after administration.

[0042] FIG14 shows a curve showing the concentration changes of the compound of Example 13 and its metabolites in the mouse brain over time from 120 to 480 minutes after administration.

[0043] FIG15 shows a graph comparing the total concentrations of the compound of Example 13 and its metabolites in the mouse brain and serum over time from 120 to 480 minutes after administration.

[0044] Figure 16 shows a curve comparison of the total concentration of the compound of Example 13 and its metabolites in the mouse brain and the total concentration in the serum and the total concentration of the compound of Example 3 in the mouse brain and the total concentration in the serum over time 120-480 minutes after administration.

[0045] FIG17 shows a curve showing the time-dependent changes in the concentration of the compound of Example 15 and its metabolites in mouse serum from 0 to 240 minutes after administration.

[0046] FIG18 shows a curve showing the concentration changes of the compound of Example 15 and its metabolites in the mouse brain over time from 0 to 240 minutes after administration.

[0047] FIG19 shows a curve comparison of the total concentration of the compound of Example 15 and its metabolites in the mouse brain and in the serum over time from 0 to 240 minutes after administration.

[0048] FIG20 shows a curve showing changes in the concentration of the compound of Example 21 and its metabolites in mouse serum over time from 120 to 480 minutes after administration.

[0049] FIG21 shows a curve showing the concentration changes of the compound of Example 21 and its metabolites in the mouse brain over time from 120 to 480 minutes after administration.

[0050] FIG22 shows a curve comparison of the total concentration of the compound of Example 21 and its metabolites in the mouse brain and in the serum over time from 120 to 480 minutes after administration.

[0051] FIG23 shows a curve showing the concentration changes of the compound of Example 22 and its metabolites in mouse serum over time from 120 to 480 minutes after administration.

[0052] FIG24 shows a curve showing the concentration changes of the compound of Example 22 and its metabolites in the mouse brain over time from 120 to 480 minutes after administration.

[0053] FIG25 shows a graph comparing the total concentrations of the compound of Example 22 and its metabolites in the mouse brain and serum over time from 120 to 480 minutes after administration.

[0054] FIG26 shows a curve comparison of the total concentration of the compound of Example 24 and its metabolites in the mouse brain and in the serum over time from 2 to 72 hours after administration.

[0055] Figure 27 shows a curve comparison of the total concentration of the compound of Example 24 and its metabolites in the mouse brain and the total concentration in the serum and the total concentration of the compound of Example 3 in the mouse brain and the total concentration in the serum over time 2-72 hours after administration.

[0056] FIG28 shows a curve showing changes in the concentration of the compound of Example 26 and its metabolites in mouse serum over time from 0 to 240 minutes after administration.

[0057] FIG29 shows a curve showing the concentration changes of the compound of Example 26 and its metabolites in the mouse brain over time from 0 to 240 minutes after administration.

[0058] FIG30 shows a graph comparing the total concentrations of the compound of Example 26 and its metabolites in the mouse brain and serum over time from 0 to 240 minutes after administration.

[0059] FIG31 shows a curve showing changes in the concentration of the compound of Example 28 and its metabolites in mouse serum over time from 120 to 480 minutes after administration.

[0060] FIG32 shows a curve showing the concentration changes of the compound of Example 28 and its metabolites in the mouse brain over time from 120 to 480 minutes after administration.

[0061] FIG33 shows a graph comparing the total concentrations of the compound of Example 28 and its metabolites in the mouse brain and serum over time from 120 to 480 minutes after administration.

[0062] Figure 34 shows a curve comparison of the total concentrations of the compound of Example 28 and its metabolites in the mouse brain and in the serum 120-480 minutes after administration and the total concentrations of the compound of Example 3 in the mouse brain and in the serum over time. DETAILED DESCRIPTION

[0063] definition

[0064] Unless otherwise stated, the following terms used in this specification and claims have the following meanings. It should be understood that, where not clearly defined herein, terms shall be given their meanings commonly known in the art. Further, it should be understood that the terms used herein are for the purpose of describing specific embodiments only and are not intended to limit the scope of the present invention in any way. Unless otherwise stated, when there is a discrepancy between the structural formula and the chemical name of the compound described herein, the structural formula shall prevail.

[0065] The group prefix "C x -C y" represents the range of carbon atoms contained in the group, wherein x and y are both integers. For example, C3-C8 cycloalkyl represents a cycloalkyl group having 3-8 carbon atoms, i.e., a cycloalkyl group having 3, 4, 5, 6, 7 or 8 carbon atoms. It should also be understood that "C3-C8" also includes any sub-range therein, such as C3-C7, C3-C6, C4-C7, C4-C6, C5-C6, etc.

[0066] As used herein, the term "alkyl" refers to a saturated monovalent hydrocarbon radical having a specified number of carbon atoms, whether straight or branched. Alkyl groups typically contain 1 to 6 carbon atoms ("C1-C6 alkyl"), preferably 1 to 5 carbon atoms ("C1-C5 alkyl"), more preferably 1 to 4 carbon atoms ("C1-C4 alkyl"), 1 to 3 carbon atoms ("C1-C3 alkyl"), or 1 to 2 carbon atoms ("C1-C2 alkyl"). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

[0067] As used herein, the term "alkoxy" refers to an alkyl group attached to the parent molecular group through an oxygen atom (i.e., "-O-alkyl"), wherein alkyl is as defined above. Alkoxy groups typically contain 1 to 6 carbon atoms ("C1-C6 alkoxy"), more preferably 1 to 4 carbon atoms ("C1-C4 alkoxy"). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, pentyloxy, and hexyloxy.

[0068] The term "halogen" as used herein refers to fluorine, chlorine, bromine, iodine, with fluorine and chlorine being preferred.

[0069] As used herein, the term "halo" refers to a substituent in which one or more hydrogen atoms are replaced by one or more identical or different halogen atoms as defined above. For example, a "halo C1-C6 alkyl" refers to a "C1-C6 alkyl" in which one or more hydrogen atoms are replaced by one or more identical or different halogen atoms, wherein "C1-C6 alkyl" is as defined above. Examples of halo C1-C6 alkyl include, but are not limited to, chloromethyl, fluoromethyl, trifluoromethyl, trichloromethyl, difluoromethyl, and dichloromethyl.

[0070] As used herein, the term "cyano" refers to a -CN group.

[0071] As used herein, the term "nitro" refers to a -NO2 group.

[0072] As used herein, the term "hydroxyl" refers to an -OH group.

[0073] As used herein, the term "aryl" refers to a monovalent hydrocarbon radical derived from a monocyclic or fused bicyclic or polycyclic ring system having well-known aromatic characteristics, wherein at least one ring contains a completely conjugated π-electron system. Fused aryl groups may include an aryl ring fused to a saturated or partially unsaturated carbocyclic or heterocyclic ring or to another aryl or heteroaryl ring, provided that the point of attachment to the parent molecule on such a fused ring system is an atom of the aromatic portion of the ring system. Aryl groups typically contain 6-14 ("C6-C 14 aryl”), more preferably 6 to 10 carbon atoms (“C6-C 10 Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and tetrahydronaphthyl.

[0074] As used herein, the term "cycloalkyl" refers to a monovalent hydrocarbon radical derived from a non-aromatic, saturated carbocyclic ring system containing a specified number of carbon atoms. Cycloalkyl groups typically contain 3 to 8 carbon atoms ("C3-C8 cycloalkyl"), preferably 3 to 7 carbon atoms ("C3-C7 cycloalkyl") or 3 to 6 carbon atoms ("C3-C6 cycloalkyl"). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0075] As used herein, the term "heteroatom" refers to an N, O, or S atom.

[0076] The term "heterocyclyl" as used herein refers to a monovalent group derived from a saturated or partially unsaturated non-aromatic ring structure containing a specified number of carbon atoms and at least one heteroatom, preferably one to four heteroatoms as ring members. Heterocyclyl includes spirocycles, bridged rings or fused rings formed with one or more other heterocycles or carbocycles, provided that the point of attachment to the parent molecule is an atom of the heterocyclic portion of such a ring system. Heterocyclyl typically contains 3 to 12 ring atoms (i.e., 3 to 12 membered heterocyclyl), preferably contains 4 to 7 ring atoms (i.e., 4 to 7 membered heterocyclyl), and most preferably contains 5 or 6 ring atoms (i.e., 5 or 6 membered heterocyclyl). Examples of heterocyclic groups include, but are not limited to, aziridinyl, oxirane, thiirane, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dihydrofuranyl, dihydrothiophenyl, dihydrooxazolyl, dihydrothiazolyl, isodihydrothiazolyl, dihydropyrrolyl, dihydroimidazolyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrazinyl, dihydropyridazinyl, piperidinyl, piperazinyl, dioxanyl, oxathianyl, azepanyl, diazepanyl, morpholinyl, thiomorpholinyl, indolinyl, and isoindolinyl.

[0077] As used herein, the term "heteroaryl" refers to a monovalent group derived from an aromatic ring structure containing the specified number of carbon atoms and at least one heteroatom, preferably one to four heteroatoms, as ring members. A heteroaryl group typically contains 5 to 12 ring atoms (a "5-12 membered heteroaryl"), preferably 5 to 10 ring atoms (a "5-10 membered heteroaryl"), and more preferably 5 or 6 ring atoms (a "5- or 6-membered heteroaryl"). A heteroaryl group may also be fused to another aryl or heteroaryl ring, or to a saturated or partially unsaturated carbocyclic or heterocyclic ring, provided that the point of attachment to the parent molecule on such a fused ring system is through an atom on the heteroaromatic portion of the ring system. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl, isoindolyl, indolizinyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisoxazolyl, Thiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, imidazopyridinyl, imidazopyrimidinyl, imidazopyridazinyl, purinyl, furopyridinyl, thienopyridinyl, benzopyranyl, quinolinyl, isoquinolinyl, quinolizinyl, quinazolinyl, quinoxalinyl, benzopyridazinyl, cinnolinyl, naphthyridinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, acridinyl, phenanthrolinyl, phenazinyl, phenoxazinyl and phenothiazinyl.

[0078] As used herein, the term "optionally" means that the situation described immediately after the term may occur, but may not occur. For example, "piperidinyl optionally substituted with methyl" encompasses both "piperidinyl not substituted with methyl" and "piperidinyl substituted with methyl".

[0079] As used herein, the term "stereoisomer" refers to isomers resulting from differences in the spatial arrangement of atoms in a molecule. Enantiomers are produced when a compound has an asymmetric carbon atom; cis- and trans-isomers are produced when a compound has a carbon-carbon double bond or a cyclic structure. The present invention includes all enantiomers, diastereomers, racemates, cis- and trans-isomers, geometric isomers, epimers, and mixtures thereof of the compounds of Formula I.

[0080] As used herein, the term "solvate" refers to a molecular complex comprising a compound of Formula I and one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). When the solvent is water, the term "hydrate" is employed.

[0081] As used herein, the term "isotopic derivative" refers to a compound that is isotopically labeled, i.e., one or more atoms in the compound are replaced by atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for incorporation into a compound include, but are not limited to, hydrogen (such as 2 H and 3 H), carbon (such as 11 C. 13 C and 14 C), chlorine (such as 36 Cl), fluorine (such as 18 F), iodine (such as 123 I. 124 I and 125 I), nitrogen (such as 13 N and 15 N), oxygen (such as 15 O. 17 O and 18 O), phosphorus (such as 32 P) and sulfur (such as 35 S). Isotopically-labeled compounds of the present invention can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-labeled reagents and / or intermediates.

[0082] As used herein, the term "pharmaceutically acceptable" refers to those substances or materials that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects, such as humans or other mammals, without excessive toxicity, irritation, allergic response, or other problems, and with a commensurate benefit / risk ratio.

[0083] The term "pharmaceutically acceptable salt" as used herein refers to a salt formed by the reaction of a pharmaceutically acceptable acid or base with a compound of formula I of the present invention, including, for example, hydrochloride, acetate, hydrobromide, sulfate, bisulfate, carbonate, bicarbonate, sulfite, phosphate, hydrogen phosphate, oxalate, malonate, valerate, borate, p-toluenesulfonate, methanesulfonate, tartrate, benzoate, lactate, citrate, maleate, fumarate, malate, salicylate, mandelate, succinate, gluconate, lactobionate, alkali metal salts (e.g., lithium, sodium, potassium, rubidium, cesium salts), alkaline earth metal salts (e.g., magnesium, calcium, strontium, barium salts), aluminum salts, etc. The salts can be prepared by methods well known to those skilled in the art.

[0084] As used herein, the term "prevent" or "prevent" means to reduce or eliminate the likelihood of a disease.

[0085] As used herein, the term "treating" refers to the complete or partial elimination of a disease and / or its attendant symptoms.

[0086] The term "subject" as used herein refers to an animal, preferably a mammal, that is an individual for intended experiment or treatment, including but not limited to primates (e.g., monkeys and humans), equines (e.g., horses), canines (e.g., dogs), felines, domestic livestock (e.g., pigs, goats, sheep, etc.), as well as domestic pets and animals kept in zoos, preferably humans.

[0087] As used herein, the term "androgen-related disease" refers to a disease that can be treated by targeting the androgen receptor or can be treated or prevented by regulating the level of androgen.

[0088] Detailed description of the technical solution of the present invention

[0089] The first aspect of the present invention provides a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopic derivative thereof:

[0090] wherein R1, R2, R3, R4, W, L and R are as defined above for the compound of formula I.

[0091] In some embodiments, L is a bond, -C(O)-, or -S(O)2-.

[0092] In some embodiments, L is a bond.

[0093] In some embodiments, L is -C(O)-.

[0094] In some embodiments, L is -S(O)2-.

[0095] In some embodiments, R is hydrogen.

[0096] In some embodiments, R is selected from C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 Aryl, 3 to 12 membered heterocyclyl, 3 to 12 membered heterocyclyl-C1-C6 alkyl, 5 to 12 membered heteroaryl and -C1-C6 alkyl-NR5R6, wherein the heterocyclyl and heteroaryl contain 1 or 2 heteroatoms independently selected from N, O or S, and the cycloalkyl, aryl, heterocyclyl and heteroaryl are optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, cyano.

[0097] In some embodiments, R is C1-C6 alkyl.

[0098] In some embodiments, R is methyl, ethyl, n-propyl, and isopropyl.

[0099] In some embodiments, R is methyl.

[0100] In some embodiments, R is C3-C8 cycloalkyl, which is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and cyano.

[0101] In some embodiments, R is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein the groups are optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and cyano.

[0102] In some embodiments, R is unsubstituted cyclopentyl.

[0103] In some embodiments, R is C6-C 10 Aryl, which is optionally substituted by 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and cyano.

[0104] In some embodiments, R is phenyl or naphthyl, which is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and cyano.

[0105] In some embodiments, R is unsubstituted phenyl.

[0106] In some embodiments, R is a 3- to 12-membered heterocyclyl, wherein the heterocyclyl contains 1 or 2 heteroatoms independently selected from N, O, or S and is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and cyano.

[0107] In some embodiments, R is a 4- to 7-membered heterocyclyl, wherein the heterocyclyl contains 1 or 2 heteroatoms independently selected from N, O, or S and is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and cyano.

[0108] In some embodiments, R is a 5- to 6-membered heterocyclyl, wherein the heterocyclyl contains 1 or 2 heteroatoms independently selected from N, O, or S and is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and cyano.

[0109] In some embodiments, R is azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dihydrofuranyl, dihydrothiophenyl, dihydrooxazolyl, dihydrothiazolyl, isodihydrothiazolidine, dihydropyrrolyl, dihydroimidazolyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrazinyl, dihydropyridazinyl, piperidinyl, piperazinyl, dioxanyl, oxathianyl, azepanyl, diazepanyl, morpholinyl, thiomorpholinyl, indolinyl, or isoindolinyl, wherein said groups are optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, cyano.

[0110] In some embodiments, R is pyrrolidinyl, piperidinyl, dihydropyridinyl, wherein said group is optionally substituted with 1 or 2 substituents independently selected from methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, iodo, cyano.

[0111] In some embodiments, R is pyrrolidinyl optionally substituted with methyl.

[0112] In some embodiments, R is piperidinyl optionally substituted with methyl.

[0113] In some embodiments, R is dihydropyridinyl optionally substituted with methyl.

[0114] In some embodiments, R is a 3- to 12-membered heterocyclyl-C1-C6 alkyl group, wherein the heterocyclyl group contains 1 or 2 heteroatoms independently selected from N, O, or S and is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and cyano.

[0115] In some embodiments, R is a 4- to 7-membered heterocyclyl-C1-C6 alkyl group, wherein the heterocyclyl group contains 1 or 2 heteroatoms independently selected from N, O, or S and is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and cyano.

[0116] In some embodiments, R is a 5- to 6-membered heterocyclyl-C1-C6 alkyl group, wherein the heterocyclyl group contains 1 or 2 heteroatoms independently selected from N, O, or S and is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and cyano.

[0117] In some embodiments, R is

[0118] In some embodiments, R is a 5- to 10-membered heteroaryl group, wherein the heteroaryl group contains 1 or 2 heteroatoms independently selected from N, O, or S and is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and cyano.

[0119] In some embodiments, R is a 5- to 6-membered heteroaryl group, wherein the heteroaryl group contains 1 or 2 heteroatoms independently selected from N, O, or S and is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and cyano.

[0120] In some embodiments, R is pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, indolizinyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, imidazopyridinyl, furopyridinyl, thienopyridinyl, benzopyranyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, benzopyridazinyl, cinnolinyl, or naphthyridinyl, wherein said groups are optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and cyano.

[0121] In some embodiments, R is unsubstituted pyridinyl.

[0122] In some embodiments, R is -C1-C6 alkyl-NR5R6, wherein R5 and R6 are each independently H or C1-C6 alkyl.

[0123] In some embodiments, R is -C1-C6 alkyl-NH2.

[0124] In some embodiments, R is -C1-C6 alkyl-NH(C1-C6 alkyl).

[0125] In some embodiments, R is -C1-C6 alkyl-N(C1-C6 alkyl)2.

[0126] In some embodiments, R is dimethylaminoethyl.

[0127] In some embodiments, R1 and R2 are each independently cyano, halogen, haloC1-C6 alkyl, nitro, or -NR5R6.

[0128] In some embodiments, R1 and R2 are each independently cyano, fluoro, chloro, bromo, iodo, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl, chloromethyl, tribromomethyl, dibromomethyl, bromomethyl, nitro, -NH2, -NH(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

[0129] In some embodiments, R1 is cyano, halo, trifluoromethyl, difluoromethyl, trichloromethyl, dichloromethyl, nitro, or -NH2.

[0130] In some embodiments, R1 is cyano, halo, trifluoromethyl, difluoromethyl, nitro, or -NH2.

[0131] In some embodiments, R1 is trifluoromethyl or halogen.

[0132] In some embodiments, R2 is cyano, halo, trifluoromethyl, difluoromethyl, trichloromethyl, dichloromethyl, nitro, or -NH2.

[0133] In some embodiments, R2 is cyano, halo, trifluoromethyl, difluoromethyl, nitro, or -NH2.

[0134] In some embodiments, R2 is cyano.

[0135] In some embodiments, W is CH.

[0136] In some embodiments, W is N.

[0137] In some embodiments, R3 and R4 are each independently hydrogen, cyano, halogen, haloC1-C6 alkyl, nitro, -NR5R6, -C(O)C1-C6 alkyl, -N(R7)C(O)C1-C6 alkyl, -N(R7)C(O)-haloC1-C6 alkyl, -C1-C6 alkylC(O)C1-C6 alkyl, -S(O)2-C1-C6 alkyl, -N(R7)-S(O)2-C1-C6 alkyl, C1-C6 alkyl or C1-C6 alkoxy.

[0138] In some embodiments, R3 and R4 are each independently hydrogen, cyano, halogen, haloC1-C6 alkyl, nitro, -NR5R6, -C(O)C1-C6 alkyl, -N(R7)C(O)C1-C6 alkyl, -N(R7)C(O)-haloC1-C6 alkyl, -S(O)2-C1-C6 alkyl or -N(R7)-S(O)2-C1-C6 alkyl.

[0139] In some embodiments, R3 and R4 are each independently hydrogen, cyano, fluoro, chloro, bromo, iodine, trifluoromethyl, difluoromethyl, trichloromethyl, dichloromethyl, nitro, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(O)C1-C6 alkyl, -NHC(O)C1-C6 alkyl, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, -S(O)2-C1-C6 alkyl, -NH-S(O)2-C1-C6 alkyl, or -N(C1-C6 alkyl)-S(O)2-C1-C6 alkyl.

[0140] In some embodiments, R3 is cyano, halogen, haloC1-C6 alkyl, nitro, -NH2, -C(O)C1-C6 alkyl, -NHC(O)C1-C6 alkyl, -NHC(O)-haloC1-C6 alkyl, -S(O)2-C1-C6 alkyl, or -NH-S(O)2-C1-C6 alkyl.

[0141] In some embodiments, R3 is cyano, fluoro, chloro, bromo, iodo, trifluoromethyl, nitro, -NH2, acetyl, acetamido, ethanesulfonyl, or ethanesulfonamido.

[0142] In some embodiments, R3 is cyano, fluoro, chloro, bromo, or iodo.

[0143] In some embodiments, R3 is cyano.

[0144] In some embodiments, R4 is hydrogen, fluoro, chloro, bromo, or iodo.

[0145] In some embodiments, R4 is hydrogen.

[0146] In some embodiments, L is a bond and R is hydrogen, such that the compound has Formula II:

[0147] In some embodiments, L is -C(O)-, such that the compound has Formula III:

[0148] In some embodiments, L is -C(O)-, and R is C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 Aryl, 3 to 12 membered heterocyclyl, 3 to 12 membered heterocyclyl-C1-C6 alkyl, 5 to 12 membered heteroaryl and -C1-C6 alkyl-NR5R6, wherein the heterocyclyl and heteroaryl contain 1 or 2 heteroatoms independently selected from N, O or S, and the cycloalkyl, aryl, heterocyclyl and heteroaryl are optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, cyano.

[0149] In some embodiments, L is -C(O)-, and R is C1-C6 alkyl.

[0150] In some embodiments, L is -C(O)-, and R is methyl, ethyl, n-propyl, or isopropyl.

[0151] In some embodiments, L is -C(O)-, and R is methyl.

[0152] In some embodiments, L is -C(O)-, and R is C3-C8 cycloalkyl, which is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and cyano.

[0153] In some embodiments, L is -C(O)-, and R is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein the groups are optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and cyano.

[0154] In some embodiments, L is -C(O)-, and R is cyclopentyl.

[0155] In some embodiments, L is -C(O)-, and R is C6-C 10 Aryl, which is optionally substituted by 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and cyano.

[0156] In some embodiments, L is -C(O)-, and R is phenyl or naphthyl, optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and cyano.

[0157] In some embodiments, L is -C(O)-, and R is unsubstituted phenyl.

[0158] In some embodiments, L is -C(O)-, and R is a 3- to 12-membered heterocyclyl, wherein the heterocyclyl contains 1 or 2 heteroatoms independently selected from N, O, or S and is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and cyano.

[0159] In some embodiments, L is -C(O)-, and R is a 4- to 7-membered heterocyclyl, wherein the heterocyclyl contains 1 or 2 heteroatoms independently selected from N, O, or S and is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and cyano.

[0160] In some embodiments, L is -C(O)-, and R is a 5- to 6-membered heterocyclyl, wherein the heterocyclyl contains 1 or 2 heteroatoms independently selected from N, O, or S and is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and cyano.

[0161] In some embodiments, L is -C(O)-, and R is azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dihydrofuranyl, dihydrothiophenyl, dihydrooxazolyl, dihydrothiazolyl, isodihydrothiazolyl, dihydropyrrolyl, dihydroimidazole, oxazolyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrazinyl, dihydropyridazinyl, piperidinyl, piperazinyl, dioxanyl, oxathianyl, azepanyl, diazepanyl, morpholinyl, thiomorpholinyl, indolinyl or isoindolinyl, wherein the group is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, cyano.

[0162] In some embodiments, L is -C(O)-, and R is pyrrolidinyl, piperidinyl, dihydropyridinyl, wherein said groups are optionally substituted with 1 or 2 substituents independently selected from methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, iodo, cyano.

[0163] In some embodiments, L is -C(O)-, and R is pyrrolidinyl optionally substituted with methyl.

[0164] In some embodiments, L is -C(O)-, and R is piperidinyl optionally substituted with methyl.

[0165] In some embodiments, L is -C(O)-, and R is dihydropyridinyl optionally substituted with methyl.

[0166] In some embodiments, L is -C(O)-, and R is a 3- to 12-membered heterocyclyl-C1-C6 alkyl group, wherein the heterocyclyl group contains 1 or 2 heteroatoms independently selected from N, O, or S and is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and cyano.

[0167] In some embodiments, L is -C(O)-, and R is a 4- to 7-membered heterocyclyl-C1-C6 alkyl, wherein the heterocyclyl contains 1 or 2 heteroatoms independently selected from N, O, or S and is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and cyano.

[0168] In some embodiments, L is -C(O)-, and R is a 5- to 6-membered heterocyclyl-C1-C6 alkyl, wherein the heterocyclyl contains 1 or 2 heteroatoms independently selected from N, O, or S and is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and cyano.

[0169] In some embodiments, L is -C(O)-, and R is

[0170] In some embodiments, L is -C(O)-, and R is a 5- to 10-membered heteroaryl, wherein the heteroaryl contains 1 or 2 heteroatoms independently selected from N, O, or S and is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and cyano.

[0171] In some embodiments, L is -C(O)-, and R is a 5- to 6-membered heteroaryl, wherein the heteroaryl contains 1 or 2 heteroatoms independently selected from N, O, or S and is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and cyano.

[0172] In some embodiments, L is -C(O)- and R is pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, indolizinyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, imidazopyridinyl, furopyridinyl, thienopyridinyl, benzopyranyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, benzopyridazinyl, cinnolinyl, or naphthyridinyl, wherein said groups are optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and cyano.

[0173] In some embodiments, L is -C(O)-, and R is pyridinyl, wherein the pyridinyl is optionally substituted with 1 or 2 substituents independently selected from methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, iodo, cyano.

[0174] In some embodiments, L is -C(O)-, and R is unsubstituted pyridinyl.

[0175] In some embodiments, L is -C(O)-, and R is -C1-C6 alkyl-NR5R6, wherein R5 and R6 are each independently H or C1-C6 alkyl.

[0176] In some embodiments, L is -C(O)-, and R is -C1-C6 alkyl-NH2.

[0177] In some embodiments, L is -C(O)-, and R is -C1-C6 alkyl-NH(C1-C6 alkyl).

[0178] In some embodiments, L is -C(O)-, and R is -C1-C6 alkyl-N(C1-C6 alkyl)2.

[0179] In some embodiments, L is -C(O)-, and R is dimethylaminoethyl.

[0180] In some embodiments, L is -S(O)2-, such that the compound has Formula IV:

[0181] In some embodiments, L is -S(O)2-, and R is C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 Aryl, 3 to 12 membered heterocyclyl, 3 to 12 membered heterocyclyl-C1-C6 alkyl, 5 to 12 membered heteroaryl and -C1-C6 alkyl-NR5R6, wherein the heterocyclyl and heteroaryl contain 1 or 2 heteroatoms independently selected from N, O or S, and the cycloalkyl, aryl, heterocyclyl and heteroaryl are optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, cyano.

[0182] In some embodiments, L is -S(O)2-, and R is C1-C6 alkyl.

[0183] In some embodiments, L is -S(O)2-, and R is methyl, ethyl, n-propyl, or isopropyl.

[0184] In some embodiments, L is -S(O)2-, and R is methyl.

[0185] In some embodiments, L is -S(O)2-, and R is C3-C8 cycloalkyl, which is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and cyano.

[0186] In some embodiments, L is -S(O)2-, and R is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein the groups are optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and cyano.

[0187] In some embodiments, L is -S(O)2-, and R is cyclopentyl.

[0188] In some embodiments, L is -S(O)2-, and R is C6-C 10Aryl, which is optionally substituted by 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and cyano.

[0189] In some embodiments, L is -S(O)2-, and R is phenyl or naphthyl, which are optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and cyano.

[0190] In some embodiments, L is -S(O)2-, and R is unsubstituted phenyl.

[0191] In some embodiments, L is -S(O)2-, and R is a 3- to 12-membered heterocyclyl, wherein the heterocyclyl contains 1 or 2 heteroatoms independently selected from N, O, or S and is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and cyano.

[0192] In some embodiments, L is -S(O)2-, and R is a 4- to 7-membered heterocyclyl, wherein the heterocyclyl contains 1 or 2 heteroatoms independently selected from N, O, or S and is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and cyano.

[0193] In some embodiments, L is -S(O)2-, and R is a 5- to 6-membered heterocyclyl, wherein the heterocyclyl contains 1 or 2 heteroatoms independently selected from N, O, or S and is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and cyano.

[0194] In some embodiments, L is -S(O)2-, and R is azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dihydrofuranyl, dihydrothiophenyl, dihydrooxazolyl, dihydrothiazolyl, isodihydrothiazolyl, dihydropyrrolyl, dihydroimidazole, oxazolyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrazinyl, dihydropyridazinyl, piperidinyl, piperazinyl, dioxanyl, oxathianyl, azepanyl, diazepanyl, morpholinyl, thiomorpholinyl, indolinyl or isoindolinyl, wherein the group is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, cyano.

[0195] In some embodiments, L is -S(O)2-, and R is pyrrolidinyl, piperidinyl, dihydropyridinyl, wherein said groups are optionally substituted with 1 or 2 substituents independently selected from methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, iodo, cyano.

[0196] In some embodiments, L is -S(O)2-, and R is pyrrolidinyl optionally substituted with methyl.

[0197] In some embodiments, L is -S(O)2-, and R is piperidinyl optionally substituted with methyl.

[0198] In some embodiments, L is -S(O)2-, and R is dihydropyridinyl optionally substituted with methyl.

[0199] In some embodiments, L is -S(O)2-, and R is a 3- to 12-membered heterocyclyl-C1-C6 alkyl group, wherein the heterocyclyl group contains 1 or 2 heteroatoms independently selected from N, O, or S and is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and cyano.

[0200] In some embodiments, L is -S(O)2-, and R is a 4- to 7-membered heterocyclyl-C1-C6 alkyl, wherein the heterocyclyl contains 1 or 2 heteroatoms independently selected from N, O, or S and is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and cyano.

[0201] In some embodiments, L is -S(O)2-, and R is a 5- to 6-membered heterocyclyl-C1-C6 alkyl, wherein the heterocyclyl contains 1 or 2 heteroatoms independently selected from N, O, or S and is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and cyano.

[0202] In some embodiments, L is -S(O)2-, and R is

[0203] In some embodiments, L is -S(O)2-, and R is a 5- to 10-membered heteroaryl, wherein the heteroaryl contains 1 or 2 heteroatoms independently selected from N, O, or S and is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and cyano.

[0204] In some embodiments, L is -S(O)2-, and R is a 5- to 6-membered heteroaryl, wherein the heteroaryl contains 1 or 2 heteroatoms independently selected from N, O, or S and is optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and cyano.

[0205] In some embodiments, L is -S(O)- and R is pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, indolizinyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, imidazopyridinyl, furopyridinyl, thienopyridinyl, benzopyranyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, benzopyridazinyl, cinnolinyl, or naphthyridinyl, wherein said groups are optionally substituted with 1 or 2 substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and cyano.

[0206] In some embodiments, L is -S(O)2-, and R is pyridinyl, wherein the pyridinyl is optionally substituted with 1 or 2 substituents independently selected from methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, iodo, and cyano.

[0207] In some embodiments, L is -S(O)2-, and R is unsubstituted pyridinyl.

[0208] In some embodiments, L is -S(O)2-, and R is -C1-C6 alkyl-NR5R6, wherein R5 and R6 are each independently H or C1-C6 alkyl.

[0209] In some embodiments, L is -S(O)2-, and R is -C1-C6 alkyl-NH2.

[0210] In some embodiments, L is -S(O)2-, and R is -C1-C6 alkyl-NH(C1-C6 alkyl).

[0211] In some embodiments, L is -S(O)2-, and R is -C1-C6 alkyl-N(C1-C6 alkyl)2.

[0212] In some embodiments, L is -S(O)2-, and R is dimethylaminoethyl.

[0213] In some embodiments, R1 and R2 are each independently cyano, halo, trifluoromethyl, difluoromethyl, nitro, or -NH2.

[0214] In some embodiments, R1 is cyano and R2 is trifluoromethyl.

[0215] In some embodiments, R1 is trifluoromethyl and R2 is cyano.

[0216] In some embodiments, R1 is nitro and R2 is trifluoromethyl.

[0217] In some embodiments, R1 is trifluoromethyl and R2 is nitro.

[0218] In some embodiments, R1 is halogen and R2 is cyano.

[0219] In some embodiments, R1 is cyano and R2 is halogen.

[0220] In some embodiments, R3 is cyano, halogen, haloC1-C6 alkyl, nitro, -NR5R6, -C(O)C1-C6 alkyl, -N(R7)C(O)C1-C6 alkyl, -N(R7)C(O)-haloC1-C6 alkyl, -C1-C6 alkylC(O)C1-C6 alkyl, -S(O)2-C1-C6 alkyl, -N(R7)-S(O)2-C1-C6 alkyl, C1-C6 alkyl or C1-C6 alkoxy, and R4 is hydrogen or halogen.

[0221] In some embodiments, R3 is cyano, fluoro, chloro, bromo, iodo, trifluoromethyl, difluoromethyl, trichloromethyl, dichloromethyl, nitro, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(O)C1-C6 alkyl, -NHC(O)C1-C6 alkyl, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, -S(O)2-C1-C6 alkyl, -NH-S(O)2-C1-C6 alkyl, or -N(C1-C6 alkyl)-S(O)2-C1-C6 alkyl, and R4 is hydrogen, fluoro, chloro, bromo, or iodo.

[0222] In some embodiments, R3 is cyano, fluoro, chloro, bromo, iodo, trifluoromethyl, nitro, -NH2, acetyl, acetamido, ethylsulfonyl, or ethylsulfamido, and R4 is hydrogen, fluoro, chloro, bromo, or iodo.

[0223] In some embodiments, R3 is cyano, fluoro, chloro, bromo, or iodo, and R4 is hydrogen, fluoro, chloro, bromo, or iodo.

[0224] In some embodiments, R3 is cyano and R4 is hydrogen.

[0225] In some embodiments, R3 is cyano and R4 is fluoro.

[0226] In some embodiments, R3 is chloro and R4 is hydrogen.

[0227] In some embodiments, a compound of Formula I is provided, wherein:

[0228] R1 and R2 are each independently cyano, halogen, trifluoromethyl, difluoromethyl, nitro or -NH2;

[0229] R3 is cyano, halogen, halo C1-C6 alkyl, nitro, -C(O)C1-C6 alkyl, -NHC(O)C1-C6 alkyl, -NHC(O)-halo C1-C6 alkyl, -S(O)2-C1-C6 alkyl or -NH-S(O)2-C1-C6 alkyl;

[0230] R4 is hydrogen or halogen;

[0231] W is CH or N;

[0232] L is a bond, -C(O)- or -S(O)2-;

[0233] R is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 Aryl, 4 to 7 membered heterocyclyl, 4 to 7 membered heterocyclyl-C1-C6 alkyl, 5 to 10 membered heteroaryl or -C1-C6 alkyl-NRR6, wherein the heterocyclyl and heteroaryl contain 1 or 2 heteroatoms independently selected from N, O or S, and the cycloalkyl, aryl, heterocyclyl and heteroaryl are optionally substituted with 1 or 2 substituents selected from C1-C6 alkyl; and

[0234] R5 and R6 are each independently H or C1-C6 alkyl.

[0235] In some embodiments, a compound of Formula I is provided, wherein:

[0236] R1 and R2 are each independently cyano, halogen, trifluoromethyl, difluoromethyl, nitro or -NH2;

[0237] R3 is cyano, halogen, halo C1-C6 alkyl, nitro, -C(O)C1-C6 alkyl, -NHC(O)C1-C6 alkyl, -NHC(O)-halo C1-C6 alkyl, -S(O)2-C1-C6 alkyl or -NH-S(O)2-C1-C6 alkyl;

[0238] R4 is hydrogen or halogen;

[0239] W is CH or N;

[0240] L is a bond; and

[0241] R is hydrogen.

[0242] In some embodiments, a compound of Formula I is provided, wherein:

[0243] R1 and R2 are each independently cyano, halogen, trifluoromethyl, difluoromethyl, nitro or -NH2;

[0244] R3 is cyano, halogen, halo C1-C6 alkyl, nitro, -C(O)C1-C6 alkyl, -NHC(O)C1-C6 alkyl, -NHC(O)-halo C1-C6 alkyl, -S(O)2-C1-C6 alkyl or -NH-S(O)2-C1-C6 alkyl;

[0245] R4 is hydrogen or halogen;

[0246] W is CH or N;

[0247] L is -C(O)-;

[0248] R is C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 Aryl, 4 to 7 membered heterocyclyl, 4 to 7 membered heterocyclyl-C1-C6 alkyl, 5 to 10 membered heteroaryl or -C1-C6 alkyl-NRR6, wherein the heterocyclyl and heteroaryl contain 1 or 2 heteroatoms independently selected from N, O or S, and the cycloalkyl, aryl, heterocyclyl and heteroaryl are optionally substituted with 1 or 2 substituents selected from C1-C6 alkyl; and

[0249] R5 and R6 are each independently H or C1-C6 alkyl.

[0250] In some embodiments, a compound of Formula I is provided, wherein:

[0251] R1 and R2 are each independently cyano, halogen, trifluoromethyl, difluoromethyl, nitro or -NH2;

[0252] R3 is cyano, halogen, halo C1-C6 alkyl, nitro, -C(O)C1-C6 alkyl, -NHC(O)C1-C6 alkyl, -NHC(O)-halo C1-C6 alkyl, -S(O)2-C1-C6 alkyl or -NH-S(O)2-C1-C6 alkyl;

[0253] R4 is hydrogen or halogen;

[0254] W is CH or N;

[0255] L is -S(O)2-;

[0256] R is C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 Aryl, 4 to 7 membered heterocyclyl, 4 to 7 membered heterocyclyl-C1-C6 alkyl, 5 to 10 membered heteroaryl or -C1-C6 alkyl-NRR6, wherein the heterocyclyl and heteroaryl contain 1 or 2 heteroatoms independently selected from N, O or S, and the cycloalkyl, aryl, heterocyclyl and heteroaryl are optionally substituted with 1 or 2 substituents selected from C1-C6 alkyl; and

[0257] R5 and R6 are each independently H or C1-C6 alkyl.

[0258] In some embodiments, a compound of Formula I is provided, wherein:

[0259] R1 and R2 are each independently cyano, halogen, trifluoromethyl or nitro;

[0260] R3 is cyano, halogen, nitro, -C(O)C1-C6 alkyl, -NHC(O)C1-C6 alkyl, -NHC(O)-halogenated C1-C6 alkyl, -S(O)2-C1-C6 alkyl or -NH-S(O)2-C1-C6 alkyl;

[0261] R4 is hydrogen or halogen;

[0262] W is CH or N;

[0263] L is a bond, -C(O)- or -S(O)2-;

[0264] R is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, 5- to 6-membered heterocyclyl, 5- to 6-membered heterocyclyl-C1-C4 alkyl, 5- to 6-membered heteroaryl, or -C1-C6 alkyl-NRR6, wherein the heterocyclyl and heteroaryl groups contain 1 or 2 heteroatoms independently selected from N, O, or S, and the cycloalkyl, aryl, heterocyclyl, and heteroaryl groups are optionally substituted with 1 or 2 substituents selected from C1-C6 alkyl; and

[0265] R5 and R6 are each independently H or C1-C4 alkyl.

[0266] In some embodiments, a compound of Formula I is provided, wherein:

[0267] R1 and R2 are each independently cyano, halogen, trifluoromethyl or nitro;

[0268] R3 is cyano, halogen, nitro, -C(O)C1-C6 alkyl, -NHC(O)C1-C6 alkyl, -NHC(O)-halogenated C1-C6 alkyl, -S(O)2-C1-C6 alkyl or -NH-S(O)2-C1-C6 alkyl;

[0269] R4 is hydrogen or halogen;

[0270] W is CH or N;

[0271] L is a bond;

[0272] R is hydrogen.

[0273] In some embodiments, a compound of Formula I is provided, wherein:

[0274] R1 and R2 are each independently cyano, halogen, trifluoromethyl or nitro;

[0275] R3 is cyano, halogen, nitro, -C(O)C1-C6 alkyl, -NHC(O)C1-C6 alkyl, -NHC(O)-halogenated C1-C6 alkyl, -S(O)2-C1-C6 alkyl or -NH-S(O)2-C1-C6 alkyl;

[0276] R4 is hydrogen or halogen;

[0277] W is CH or N;

[0278] L is -C(O)-;

[0279] R is C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, 5- to 6-membered heterocyclyl, 5- to 6-membered heterocyclyl-C1-C4 alkyl, 5- to 6-membered heteroaryl, or -C1-C6 alkyl-NRR6, wherein the heterocyclyl and heteroaryl groups contain 1 or 2 heteroatoms independently selected from N, O, or S, and the cycloalkyl, aryl, heterocyclyl, and heteroaryl groups are optionally substituted with 1 or 2 substituents selected from C1-C6 alkyl; and

[0280] R5 and R6 are each independently H or C1-C4 alkyl.

[0281] In some embodiments, a compound of Formula I is provided, wherein:

[0282] R1 and R2 are each independently cyano, halogen, trifluoromethyl or nitro;

[0283] R3 is cyano, halogen, nitro, -C(O)C1-C6 alkyl, -NHC(O)C1-C6 alkyl, -NHC(O)-halogenated C1-C6 alkyl, -S(O)2-C1-C6 alkyl or -NH-S(O)2-C1-C6 alkyl;

[0284] R4 is hydrogen or halogen;

[0285] W is CH or N;

[0286] L is -S(O)2-;

[0287] R is C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, 5- to 6-membered heterocyclyl, 5- to 6-membered heterocyclyl-C1-C4 alkyl, 5- to 6-membered heteroaryl, or -C1-C6 alkyl-NRR6, wherein the heterocyclyl and heteroaryl groups contain 1 or 2 heteroatoms independently selected from N, O, or S, and the cycloalkyl, aryl, heterocyclyl, and heteroaryl groups are optionally substituted with 1 or 2 substituents selected from C1-C6 alkyl; and

[0288] R5 and R6 are each independently H or C1-C4 alkyl.

[0289] In some embodiments, a compound of Formula I is provided, wherein:

[0290] R1 is trifluoromethyl;

[0291] R2 is a cyano group;

[0292] R3 is cyano or halogen;

[0293] R4 is hydrogen or halogen;

[0294] W is CH or N;

[0295] L is a bond, -C(O)- or -S(O)2-;

[0296] R is hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopentyl, phenyl, piperidinyl optionally substituted by methyl, pyrrolidinyl optionally substituted by methyl, dihydropyridinyl optionally substituted by methyl, pyridinyl, dimethylaminoethyl or

[0297] In some embodiments, provided is a compound selected from the group consisting of:

[0298] The second aspect of the present invention provides a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopic derivative thereof and one or more pharmaceutically acceptable carriers.

[0299] In some embodiments, the pharmaceutical composition comprises 0.1% to 99.5% by weight of a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, or isotopic derivative thereof as an active ingredient, preferably 0.5% to 99.5% by weight, more preferably 1% to 50% by weight, for example 1%, 1.5%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, or 50% by weight of the active ingredient. The remainder of the pharmaceutical composition is a pharmaceutically acceptable carrier.

[0300] In some embodiments, the pharmaceutical composition comprises two, three or more pharmaceutically acceptable carriers. The pharmaceutically acceptable carrier includes conventional pharmaceutical carriers in the pharmaceutical field, such as diluents, fillers, adhesives, disintegrants, lubricants, wetting agents, solubilizers, solvents, colorants, spices, absorption promoters, surfactants, adsorption carriers, etc., examples of which include but are not limited to starch, pregelatinized starch, sodium carboxymethyl starch, powdered sugar, lactose, calcium phosphate, magnesium stearate, talc, micropowdered silica gel, dextrin, cellulose and its derivatives (such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose, etc.), microcrystalline cellulose, mannitol, sorbitol, polysorbate 80, polyethylene glycol, water, water for injection, normal saline, glucose solution, etc. The pharmaceutical composition may also include various other commonly used additives, such as preservatives, emulsifiers, suspending agents, flavoring agents, etc.

[0301] The pharmaceutical composition can be prepared into any suitable pharmaceutically acceptable dosage form by any conventional technology in the art, including but not limited to tablets, capsules, pills, granules, syrups, injections, solutions, suspensions, powders (including sterile powders for injection), etc. The pharmaceutical composition of the present invention can be applied to a subject (such as a human or non-human mammal) by any route of administration, including, for example, oral, intravenous, intraperitoneal, intramuscular, topical, transdermal, ocular, nasal, inhalation, subcutaneous, buccal, sublingual, rectal, etc. The effective amount of the compound of formula I of the present invention or a pharmaceutically acceptable salt thereof depends on a variety of factors, including but not limited to: the specific compound to be administered; the species, size, age and general health of the mammal; the severity of the disease; the response of the individual patient; the mode of administration; the bioavailability characteristics of the formulation administered; the selected dosage regimen; the use of other concomitant drugs, etc., which can usually be determined by the attending physician according to conventional practice. In general, the effective amount is usually in the range of about 0.001 to about 100 mg / kg body weight / day, preferably about 0.01 to about 50 mg / kg body weight / day. In some cases, dosage levels below the lower limit of the aforementioned range may be more than sufficient, while in other cases, it may be necessary to use larger doses without causing any harmful side effects, with such larger doses generally being divided into several smaller doses for administration throughout the day.

[0302] The third aspect of the present invention provides a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopic derivative thereof, or a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopic derivative thereof and one or more pharmaceutically acceptable carriers, which is used to prevent and / or treat androgen-related diseases, particularly central nervous system diseases.

[0303] A fourth aspect of the present invention provides a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopic derivative thereof, or a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopic derivative thereof and one or more pharmaceutically acceptable carriers for preventing and / or treating androgen-related diseases, particularly central nervous system diseases.

[0304] A fifth aspect of the present invention provides the use of a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopic derivative thereof, or a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopic derivative thereof and one or more pharmaceutically acceptable carriers in the preparation of a medicament for preventing and / or treating androgen-related diseases, particularly central nervous system diseases.

[0305] A sixth aspect of the present invention provides a method for preventing and / or treating androgen-related diseases, particularly central nervous system diseases, in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopic derivative thereof, or a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopic derivative thereof and one or more pharmaceutically acceptable carriers.

[0306] In the above aspects 3 to 6, the central nervous system disease is dementia (including Alzheimer's disease), cognitive deficits in schizophrenia, Parkinson's disease, Huntington's disease, depression, anxiety, stroke, cerebral ischemia, amyotrophic lateral sclerosis, traumatic brain injury, fragile X syndrome, Rett syndrome, brain tumor or obesity.

[0307] In some embodiments, the central nervous system disease is Alzheimer's disease.

[0308] The compounds or pharmaceutical compositions of the present invention can be administered to a subject (e.g., a human or non-human mammal) by any route of administration, including, for example, oral, intravenous, intraperitoneal, intramuscular, topical, transdermal, ocular, nasal, inhalation, subcutaneous, buccal, sublingual, rectal, and the like.

[0309] The attending physician may adjust the dosage and frequency of administration of the compound of the present invention or pharmaceutical composition, taking into account factors such as the patient's age, general health, weight, and severity of the symptoms to be treated. In general, the total daily dose of the compound of the present invention or pharmaceutical composition is typically from about 0.1 to about 1000 mg of active ingredient / day, such as from about 1 to about 800 mg / day, from about 10 to about 600 mg / day, from about 50 to about 500 mg / day, administered in a single dose or 2, 3, or 4 divided doses.

[0310] The main beneficial effects of the compounds of the present invention include the following aspects:

[0311] (1) The compounds of the present invention have good ability to bind to androgen receptors, and some of them show nanomolar protein affinity (KD);

[0312] (2) The compounds of the present invention have good androgen receptor agonist activity, with some compounds showing nanomolar agonist activity and achieving a maximum agonist activity comparable to that of dihydrotestosterone;

[0313] (3) The compounds of the present invention have good blood-brain barrier permeability, can penetrate the blood-brain barrier well, and maintain effective concentrations in the brain for a long time.

[0314] The novel N-aryl propionamide ester compound of the present invention is a novel non-steroidal androgen receptor modulator that can penetrate the blood-brain barrier. This series of compounds not only has good ability to bind to androgen receptors and regulate androgen receptors, but also can well penetrate the blood-brain barrier, and has the potential to become a therapeutic drug for central nervous system diseases targeting androgen receptors.

[0315] General Methods for Preparing Compounds of the Invention

[0316] Compounds of Formula I can be prepared from commercially available or readily prepared starting materials according to synthesis and purification methods well known to those skilled in the art of organic synthesis. Exemplary methods for preparing compounds of Formula I are described in the following schemes and examples. It should be understood that these exemplary methods do not limit the present invention in any way, and those skilled in the art of organic synthesis will appreciate alternative synthetic routes.

[0317] Option 1

[0318] Scheme 1 illustrates a general method for preparing compounds of Formula I wherein L is a bond and R is hydrogen (ie, compounds of Formula II described above), wherein each variable R1, R2, R3, R4, and W are as defined above for compounds of Formula I.

[0319] Step 1: Compound 1 (commercially available) reacts with SOCl2 at 0°C in an anhydrous solvent to give compound 2.

[0320] Step 2: Compound 2 reacts with compound 3 (commercially available) at 0°C in an anhydrous solvent in the presence of a base to produce compound 4.

[0321] Step 3: Compound 4 is converted into compound 5 by heating in an anhydrous solvent in the presence of a base.

[0322] Step 4: Compound 5 is reacted with compound 6 (commercially available) in the presence of a base in an anhydrous solvent to obtain a compound of formula II.

[0323] In each of the above reaction steps, the base is selected from sodium tert-butoxide, sodium methoxide, potassium tert-butoxide, trimethylammonium hydroxide, guanidines, diazabicyclo, triethylamine, pyridine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, etc., and the anhydrous solvent is selected from pyridine, tetrahydrofuran, acetonitrile, toluene, acetone, 2-butanone, ethyl acetate, dioxane, N,N-dimethylformamide, and N,N-dimethylacetamide.

[0324] Option 2

[0325] Scheme 2 illustrates a general method for preparing compounds of Formula I wherein L is -C(O)- (ie, compounds of Formula III described above), wherein the variables R1, R2, R3, R4, W and R are as defined above for compounds of Formula I.

[0326] The compound of formula II is prepared as described in Scheme 1, and reacted with a carboxylic acid compound (which may also be the corresponding acid anhydride or acid chloride) in the presence of a base in an anhydrous solvent at 0°C to obtain the compound of formula III. The base is selected from sodium tert-butoxide, sodium methoxide, potassium tert-butoxide, trimethylammonium hydroxide, guanidines, diazabicyclo, triethylamine, pyridine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, and the like, and the anhydrous solvent is selected from pyridine, tetrahydrofuran, acetonitrile, toluene, acetone, 2-butanone, ethyl acetate, dioxane, N,N-dimethylformamide, and N,N-dimethylacetamide.

[0327] Option 3

[0328] Scheme 3 illustrates a general method for preparing compounds of Formula I wherein L is -S(O)2- (ie, compounds of Formula IV described above), wherein the variables R1, R2, R3, R4, W and R are as defined above for compounds of Formula I.

[0329] The compound of formula II is prepared as described in Scheme 1, and reacted with an acyl chloride compound in the presence of a base in an anhydrous solvent at 0°C to obtain a compound of formula IV. The base is selected from sodium tert-butoxide, sodium methoxide, potassium tert-butoxide, trimethylammonium hydroxide, guanidines, diazabicyclo, triethylamine, pyridine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, and the like, and the anhydrous solvent is selected from pyridine, tetrahydrofuran, acetonitrile, toluene, acetone, 2-butanone, ethyl acetate, dioxane, N,N-dimethylformamide, and N,N-dimethylacetamide.

[0330] Example

[0331] The present invention will be further specifically described below with reference to examples. It is apparent that the examples described are only a part of the present invention, rather than all of it. These examples are merely illustrative of the present invention and should not be construed as limiting the scope of protection of the present invention. Based on the examples of the present invention, all other technical solutions obtained by those skilled in the art without creative work fall within the scope of protection of the present invention.

[0332] In the examples, the abbreviation THF stands for tetrahydrofuran, DMSO-d6 stands for deuterated dimethyl sulfoxide, DMSO stands for dimethyl sulfoxide, CDCl3 stands for deuterated chloroform, eq stands for equivalent, HPLC stands for high pressure liquid chromatography, PPh3 stands for triphenylphosphine, PCy3 stands for tricyclohexylphosphine, K3PO4 stands for tripotassium phosphate, DMF stands for dimethylformamide, Pd(PPh3)4 stands for tetrakis(triphenylphosphine)palladium, and DME stands for ethylene glycol dimethyl ether.

[0333] 1 H NMR measurements were performed using a Bruker AVANCE II 400 MHz nuclear magnetic resonance instrument, where s represents a singlet, bs or brs represents a broad singlet, d represents a doublet, t represents a triplet, q represents a quartet, dd represents a doublet of doublets, dt represents a doublet of triplets, dq represents a doublet of quartets, m represents a multiplet, and Ar represents an aromatic group. Mass spectrometry was performed using a Bruker amaZon SL mass spectrometer. High-resolution mass spectrometry was performed using a Thermo TSQ. High-pressure liquid chromatography was performed using an Agilent 1260 Infinity II. Thin-layer chromatography was performed using Silica gel 60F254 plates (Merck).

[0334] I. Compound Preparation Examples

[0335] Example 1 Preparation of (S)-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-2-hydroxy-2-methyl-3-((6-(trifluoromethyl)pyrimidin-4-yl)oxy)propionamide

[0336] First and second step reactions

[0337] Under nitrogen protection, (2R)-3-bromo-2-hydroxy-2-methylpropionic acid (2.7mmol) was added to 10mL of anhydrous THF, and then dichlorothionyl (3.28mmol) was slowly added under ice bath conditions and the temperature in the reaction vessel was kept below 0°C. The reaction solution was gradually warmed to room temperature and reacted for 1.5 hours. The reaction solution was placed back under ice bath conditions, triethylamine (3.55mmol) was added dropwise, and the temperature in the reaction vessel was kept below 0°C. Subsequently, a THF solution (2mL) of 5-amino-3-(trifluoromethyl)pyridine cyanide (2.7mmol) was added dropwise, and the temperature in the reaction vessel was continued to be kept below 0°C. After the addition was complete, the mixture was slowly warmed to room temperature, then heated to 50°C and reacted for 2 hours. TLC showed that the reaction was complete, and the reaction solution cooled to room temperature was quenched with water and extracted with 40mL of ethyl acetate. The organic phase was washed with water and saturated brine. Anhydrous sodium sulfate was added for drying, filtered, and evaporated under reduced pressure to obtain compound (R)-3-bromo-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-2-hydroxy-2-methylpropionamide.

[0338] 1 H NMR (400MHz, DMSO-d6) δ10.83(s,1H,NH),9.41(d,J=2.2Hz,1H,CH),8.91(d,J=2.3Hz,1H,CH) ,6.53(s,1H,CH),3.93–3.80(m,2H,1 / 2*CH2),3.71–3.52(m,2H,1 / 2*CH2),1.50(s,3H,CH3). LRMS(-ESI)m / z:350.0 / 352.0,[(MH)-,99 / 100%].

[0339] The third and fourth steps

[0340] Under nitrogen, (R)-3-bromo-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-2-hydroxy-2-methylpropionamide (0.7 mmol) and 4-hydroxy-6-(trifluoromethyl)pyrimidine (0.8 mmol) were added to anhydrous butanone (10 mL) and stirred to dissolve. Anhydrous KCO (2.1 mmol) was added, and the temperature was controlled at 80-85°C, with stirring for 3 hours. TLC indicated the reaction was complete, and the KCO was removed by filtration. The filtrate was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure, and then separated by column chromatography to yield the target compound (S)-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-2-hydroxy-2-methyl-3-((6-(trifluoromethyl)pyrimidin-4-yl)oxy)propionamide. The product was obtained as a white powdery solid in a 65% yield.

[0341] 1 H NMR (400MHz, DMSO-d6) δ10.74(s,1H,NH),9.27(d,J=2.3Hz,1H,CH),8.76(d,J=2.3Hz,1H,C H),8.49(s,1H,CH),6.90(s,1H,CH),6.61(br,1H,OH),4.23(s,2H,CH2),1.39(s,3H,CH3). LRMS(-ESI)433.99m / z: [(MH)-,100%].

[0342] Example 2 Preparation of (S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-((6-(trifluoromethyl)pyrimidin-4-yl)oxy)propionamide

[0343] First and second step reactions

[0344] Under nitrogen, (2R)-3-bromo-2-hydroxy-2-methylpropionic acid (2.7 mmol) was added to 10 mL of anhydrous THF. Thionyl chloride (3.28 mmol) was then slowly added in an ice bath, maintaining the reaction vessel temperature below 0°C. The reaction solution was gradually warmed to room temperature and allowed to react for 1.5 hours. The reaction solution was returned to an ice bath, and triethylamine (3.55 mmol) was added dropwise, maintaining the reaction vessel temperature below 0°C. Subsequently, a THF solution (2 mL) of 4-cyano-3-trifluoromethyl-aniline (2.7 mmol) was added dropwise, continuing to maintain the reaction vessel temperature below 0°C. After the addition was complete, the mixture was slowly warmed to room temperature and then heated to 50°C for 2 hours. TLC indicated the reaction was complete. The reaction solution, cooled to room temperature, was quenched with water, and extracted with 40 mL of ethyl acetate. The organic phase was washed with water and saturated brine. Anhydrous sodium sulfate was added for drying, filtered, and evaporated under reduced pressure to obtain compound (R)-3-bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropionamide.

[0345] 1H NMR (500MHz, DMSO-d6) δ10.54(s,1H,NH),8.55(d,J=2.2Hz,1H,CH),8.31(dd,J=8.6,2.1Hz,1H,CH),8.12(d,J=8. 6Hz,1H,CH),6.42(s,1H,CH),3.83(d,J=10.4Hz,1H,1 / 2*CH2),3.59(d,J=10.4Hz,1H,1 / 2*CH2),1.49(s,3H,CH3). δLRMS(+ESI)m / z:349.0 / 351.0,[(MH)-,99 / 100%].

[0346] The third and fourth steps

[0347] Under nitrogen, (R)-3-bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropionamide (0.7 mmol) and 4-hydroxy-6-(trifluoromethyl)pyrimidine (0.8 mmol) were added to anhydrous butanone (10 mL) and stirred to dissolve. Anhydrous K₂CO₃ (2.1 mmol) was added, and the temperature was controlled at 80-85°C and stirred for 3 hours. TLC indicated the reaction was complete, and the K₂CO₃ was removed by filtration. The filtrate was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure and separated by column chromatography to yield the target compound (S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-3-((6-(trifluoromethyl)pyrimidin-4-yl)oxy)propionamide. The product was obtained as a white powdery solid in a 60% yield.

[0348] 1 H NMR (400MHz, DMSO-d6) δ10.49(s,1H,NH),8.48(s,1H,CH),8.41(d,J=2.1Hz,1H,CH),8.20(dd,J=8.6,2.1Hz,1H,CH),8.08(d,J=8. 6Hz,1H,CH),6.90(s,1H,CH),6.50(s,1H,OH),4.28(d,J=13.6Hz,1H,1 / 2*CH2),4.19(d,J=13.6Hz,1H,1 / 2*CH2),1.37(s,3H,CH3). LRMS(-ESI)433.12m / z:[(MH)-,100%].

[0349] Example 3 Preparation of (S)-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropionamide

[0350] Under nitrogen, (R)-3-bromo-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-2-hydroxy-2-methylpropionamide (0.3 mmol) and 4-hydroxybenzonitrile (0.3 mmol) were added to anhydrous butanone (10 mL) and stirred to dissolve. Anhydrous K₂CO₃ (0.8 mmol) was added, and the temperature was controlled at 80-85°C and stirred for 3 hours. TLC indicated the reaction was complete. The K₂CO₃ was removed by filtration, and the filtrate was washed with water and saturated brine, then dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure and separated by column chromatography to yield the target compound (S)-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropionamide as a white powdery solid in a 65% yield.

[0351] 1 H NMR (400MHz, DMSO-d6) δ10.88(s,1H,NH),9.39(d,J=2.2Hz,1H,CH),8.88(d,J=2.3Hz,1H,CH),7.81–7.64(m,2H,2*CH),7. 16–7.00(m,2H,2*CH),6.44(s,1H,OH),4.32(d,J=9.9Hz,1H,1 / 2*CH2),4.09(d,J=9.9Hz,1H,1 / 2*CH2),1.44(s,3H,CH3). LRMS(+ESI)389.04m / z:[(M+H)+,100%].

[0352] Example 4 Preparation of (S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-((6-cyanopyridin-3-yl)oxy)-2-hydroxy-2-methylpropionamide

[0353] Under nitrogen, (R)-3-bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropionamide (0.3 mmol) and 5-hydroxypicolinonitrile (0.3 mmol) were added to anhydrous butanone (10 mL) and stirred to dissolve. Anhydrous KCO (0.8 mmol) was added, and the temperature was controlled at 80-85°C, with stirring for 3 hours. TLC indicated the reaction was complete, and the KCO was removed by filtration. The filtrate was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure, and the target compound was obtained after column chromatography as a white powdery solid in a 75% yield.

[0354] 1 H NMR (400MHz, DMSO-d6) δ10.61(s,1H,NH),8.53(d,J=2.1Hz,1H,CH),8.40(d,J=2.9Hz,1H,CH),8.29(dd,J=8.6,2.1Hz,1H,CH),8.09(d,J=8.6Hz,1H ,CH),7.97(d,J=8.7Hz,1H,CH),7.61(dd,J=8.8,3.0Hz,1H,CH),6.40(s,1H,OH),4.43(d,J=10.2Hz,1H,1 / 2*CH2),4.18(d,J=10.1Hz,1H,1 / 2*CH2). LRMS(+ESI)390.05m / z:[(M+H)+,100%].

[0355] Example 5 Preparation of (S)-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-3-((6-cyanopyridin-3-yl)oxy)-2-hydroxy-2-methylpropionamide

[0356] Under nitrogen, (R)-3-bromo-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-2-hydroxy-2-methylpropionamide (0.3 mmol) and 5-hydroxypyridinecarbonitrile (0.3 mmol) were added to anhydrous butanone (10 mL) and stirred to dissolve. Anhydrous KCO (0.8 mmol) was added, and the temperature was controlled at 80-85°C, with stirring for 3 hours. TLC indicated the reaction was complete, and the KCO was removed by filtration. The filtrate was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure, and the target compound was obtained after column chromatography as a white powdery solid in a 68% yield.

[0357] 1 H NMR (400MHz, DMSO-d6) δ10.89(s,1H,NH),9.39(d,J=2.3Hz,1H,CH),8.88(d,J=2.3Hz,1H,CH),8.41(dd,J=3.0,0.6Hz,1H,CH),7.98(dd,J =8.7,0.7Hz,1H,CH),7.61(dd,J=8.8,2.9Hz,1H,CH),6.49(s,1H,OH),4.42(d,J=10.1Hz,1H,1 / 2*CH2),4.20(d,J=10.2Hz,1H,1 / 2*CH2). LRMS(-ESI)390.05m / z:[(MH)-,100%].

[0358] Example 6 Preparation of (S)-3-(4-chlorophenoxy)-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-2-hydroxy-2-methylpropionamide

[0359] Under nitrogen, (R)-3-bromo-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-2-hydroxy-2-methylpropionamide (0.3 mmol) and 4-chlorophenol (0.3 mmol) were added to anhydrous butanone (10 mL) and stirred to dissolve. Anhydrous K2CO3 (0.8 mmol) was added, and the temperature was controlled at 80-85°C, with stirring for 3 hours. TLC indicated the reaction was complete, and the K2CO3 was removed by filtration. The filtrate was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure, and then separated by column chromatography to yield the target compound (S)-3-(4-chlorophenoxy)-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-2-hydroxy-2-methylpropionamide. The product was obtained as a white powdery solid in a 77% yield.

[0360] 1H NMR(500MHz,DMSO-d6)δ10.88(s,1H,NH),9.44–9.39(m,1H,CH),8.91(t,J=1.6Hz,1H,CH),7.33–7.25(m,2H,2*CH),6.99– 6.92(m,2H,2*CH),6.40(s,1H,CH),4.23(d,J=9.7Hz,1H,1 / 2*CH),4.00(d,J=9.8Hz,1H,1 / 2*CH),1.47–1.43(m,3H,CH3). LRMS(-ESI)m / z:398.0 / 399.0 / 400.0,[(MH)-,100 / 20 / 33%].

[0361] Example 7 Preparation of (S)-3-((6-chloropyridin-3-yl)oxy)-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-2-hydroxy-2-methylpropionamide

[0362] Under nitrogen, (R)-3-bromo-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-2-hydroxy-2-methylpropionamide (0.3 mmol) and 2-chloro-5-hydroxypyridine (0.3 mmol) were added to anhydrous butanone (10 mL) and stirred to dissolve. Anhydrous KCO (0.8 mmol) was added, and the temperature was controlled at 80-85°C, with stirring for 3 hours. TLC indicated the reaction was complete, and the KCO was removed by filtration. The filtrate was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure, and the target compound was obtained after column chromatography as a white powdery solid in a 75% yield.

[0363] 1 H NMR (400MHz, DMSO-d6) δ10.87(s,1H,NH),9.39(d,J=2.2Hz,1H,CH),8.89(d,J=2.2Hz,1H,CH),8.10(d,J=3.1Hz,1H,CH),7.52–7.43(m, 1H,CH),7.39(d,J=8.8Hz,1H,CH),6.43(s,1H,OH),4.32(d,J=10.0Hz,1H,1 / 2*CH2),4.08(d,J=10.0Hz,1H,1 / 2*CH2),1.43(s,3H,CH3). LRMS(+ESI)401.1m / z:[(M+H)+,100%].

[0364] Example 8 Preparation of (S)-3-(4-cyano-3-fluorophenoxy)-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-2-hydroxy-2-methylpropionamide

[0365] Under nitrogen, (R)-3-bromo-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-2-hydroxy-2-methylpropionamide (0.3 mmol) and 2-fluoro-4-hydroxybenzonitrile (0.3 mmol) were added to anhydrous butanone (10 mL) and stirred to dissolve. Anhydrous K₂CO₃ (0.8 mmol) was added, and the temperature was controlled at 80-85°C, with stirring for 3 hours. TLC indicated the reaction was complete, and the K₂CO₃ was removed by filtration. The filtrate was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure, and the target compound was obtained after column chromatography as a white powdery solid in an 81% yield.

[0366] 1 H NMR (400MHz, DMSO) δ10.89(s,1H,NH),9.42(d,J=2.3Hz,1H,CH),8.91(d,J=2.3Hz,1H,CH),7.85–7.76(m,1H,CH),7.19(dd,J=11.9,2.4Hz,1 H, CH), 6.97 (dd, J = 8.8, 2.4Hz, 1H, CH), 6.49 (s, 1H, OH), 4.38 (d, J = 10.1Hz, 1H, 1 / 2*CH2), 4.15 (d, J = 10.1Hz, 1H, 1 / 2*CH2), 1.46 (s, 3H, CH3). LRMS(-ESI)407.0m / z:[(MH)-,100%].

[0367] Example 9 Preparation of (S)-N-(5-chloro-6-cyanopyridin-3-yl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropionamide

[0368] First and second step reactions

[0369] Under nitrogen protection, (2R)-3-bromo-2-hydroxy-2-methylpropionic acid (2.7mmol) was added to 10mL of anhydrous THF, and then dichlorothionyl (3.28mmol) was slowly added under ice bath conditions and the temperature in the reaction vessel was kept below 0°C. The reaction solution was gradually warmed to room temperature and reacted for 1.5 hours. The reaction solution was placed back under ice bath conditions, triethylamine (3.55mmol) was added dropwise, and the temperature in the reaction vessel was kept below 0°C. Subsequently, a THF solution (2mL) of 5-amino-3-chloro-2-pyridinecarbonitrile (2.7mmol) was added dropwise, and the temperature in the reaction vessel was continued to be kept below 0°C. After the addition was complete, the mixture was slowly warmed to room temperature, then heated to 50°C and reacted for 2 hours. TLC showed that the reaction was complete, and the reaction solution cooled to room temperature was quenched with water and extracted with 40mL of ethyl acetate. The organic phase was washed with water and saturated brine. Anhydrous sodium sulfate was added for drying, filtered, and evaporated under reduced pressure to obtain compound (R)-3-bromo-N-(5-chloro-6-cyanopyridin-3-yl)-2-hydroxy-2-methylpropionamide.

[0370] 1H NMR (400MHz, DMSO-d6) δ10.71(s,1H,NH),9.16(d,J=2.1Hz,1H,CH),8.71(d,J=2.1Hz,1H,CH),6.5 4(s,1H,OH),3.88(d,J=10.4Hz,1H,1 / 2*CH2),3.65(d,J=10.6Hz,1H,1 / 2*CH2),1.55(s,3H,CH3). δLRMS(-ESI)315.9 / 317.9 / 319.9m / z: [(MH)-,78% / 100% / 33%].

[0371] The third and fourth steps

[0372] Under nitrogen, (R)-3-bromo-N-(5-chloro-6-cyanopyridin-3-yl)-2-hydroxy-2-methylpropionamide (0.7 mmol) and 4-hydroxybenzonitrile (0.8 mmol) were added to anhydrous butanone (10 mL) and stirred to dissolve. Anhydrous K₂CO₃ (2.1 mmol) was added, and the temperature was controlled at 80-85°C and stirred for 3 hours. TLC indicated the reaction was complete. The K₂CO₃ was removed by filtration, and the filtrate was washed with water and saturated brine, then dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure and separated by column chromatography to yield the target compound (S)-N-(5-chloro-6-cyanopyridin-3-yl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropionamide as a white powdery solid in a 62% yield.

[0373] δLRMS(-ESI)355.0m / z: [(MH)-,100%].

[0374] Example 10 Preparation of (S)-N-(5-chloro-6-cyanopyridin-3-yl)-3-((6-cyanopyridin-3-yl)oxy)-2-hydroxy-2-methylpropionamide

[0375] Under nitrogen, (R)-3-bromo-N-(5-chloro-6-cyanopyridin-3-yl)-2-hydroxy-2-methylpropionamide (0.7 mmol) and 5-hydroxypyridine-2-carbonitrile (0.8 mmol) were added to anhydrous butanone (10 mL) and stirred to dissolve. Anhydrous K2CO3 (2.1 mmol) was added, and the temperature was controlled at 80-85°C and stirred for 3 hours. TLC indicated the reaction was complete. The K2CO3 was removed by filtration, and the filtrate was washed with water and saturated brine, then dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure and separated by column chromatography to yield the target compound (S)-N-(5-chloro-6-cyanopyridin-3-yl)-3-((6-cyanopyridin-3-yl)oxy)-2-hydroxy-2-methylpropionamide. The product was obtained as a white powdery solid in a 55% yield.

[0376] δLRMS(-ESI)356.1m / z: [(MH)-,100%].

[0377] Example 11 Preparation of (S)-1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-3-((6-cyanopyridin-3-yl)oxy)-2-methyl-1-oxopropan-2-yl nicotinate

[0378] Under the protection of nitrogen and in an ice bath, (S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-((6-cyanopyridin-3-yl)oxy)-2-hydroxy-2-methylpropionamide (0.8 mmol), triethylamine (1.9 mmol) and 2,4,6-trichlorobenzoyl chloride (1.9 mmol) were added to toluene (10 mL) and stirred to dissolve. 4-Dimethylaminopyridine (3.8 mmol) and nicotinic acid (1.6 mmol) were then added to the solution, the temperature was controlled below 0°C, and the reaction was stirred for 30 minutes. TLC showed that the reaction was complete, and the reaction solution was added to saturated sodium bicarbonate aqueous solution to quench it, and ethyl acetate was added for extraction. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The crude product was obtained after distillation under reduced pressure, and the above-mentioned target compound was obtained after separation by chromatographic column. It was a white powdery solid with a yield of 81%.

[0379] 1H NMR(400MHz,DMSO-d6)δ10.59(s,1H,NH),9.08(dd,J=2.3,0.8Hz,1H,CH),8.84(d d,J=4.8,1.7Hz,1H,CH),8.51(d,J=2.8Hz,1H,CH),8.31–8.22(m,2H,2*CH),8.18 –8.05(m,2H,2*CH),8.00(d,J=8.7Hz,1H,CH),7.72(dd,J=8.8,2.9Hz,1H,CH),7. 58(ddd,J=8.0,4.9,0.9Hz,1H,CH), 4.76(q,J=10.8Hz,2H,CH2),1.87(s,3H,CH3). LRMS(+ESI)496.13m / z:[(M+H)+,100%].

[0380] Example 12 Preparation of (S)-1-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-3-((6-cyanopyridin-3-yl)oxy)-2-methyl-1-oxopropan-2-ylnicotinate

[0381] Under the protection of nitrogen and in an ice bath, (S)-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-3-((6-cyanopyridin-3-yl)oxy)-2-hydroxy-2-methylpropionamide (0.1 mmol), triethylamine (0.2 mmol) and 2,4,6-trichlorobenzoyl chloride (0.2 mmol) were added to toluene (2 mL) and stirred to dissolve. 4-Dimethylaminopyridine (0.4 mmol) and nicotinic acid (0.4 mmol) were then added to the solution, the temperature was controlled below 0°C, and the reaction was stirred for 30 minutes. TLC showed that the reaction was complete, and the reaction solution was added to saturated sodium bicarbonate aqueous solution to quench it, and ethyl acetate was added for extraction. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The crude product was obtained after distillation under reduced pressure, and the target compound was obtained after separation by chromatographic column. It was a white powdery solid with a yield of 3%.

[0382] LRMS(-ESI)495.0m / z:[(MH)-,100%].

[0383] Example 13 Preparation of (S)-1-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-3-(4-cyanophenoxy)-2-methyl-1-oxopropan-2-yl nicotinate

[0384] Under nitrogen protection and in an ice bath, (S)-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropionamide (0.8 mmol), triethylamine (1.9 mmol), and 2,4,6-trichlorobenzoyl chloride (1.9 mmol) were added to toluene (10 mL) and stirred to dissolve. 4-Dimethylaminopyridine (3.8 mmol) and nicotinic acid (1.6 mmol) were then added to the solution, the temperature was controlled below 0°C, and the reaction was stirred for 30 minutes. TLC showed that the reaction was complete, and the reaction solution was added to saturated sodium bicarbonate aqueous solution to quench it and extracted with ethyl acetate. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The crude product was obtained after distillation under reduced pressure, and the target compound was obtained after separation by chromatographic column. It was a white powdery solid with a yield of 75%.

[0385] 1 H NMR (400MHz, DMSO-d6) δ10.83(s,1H,NH),9.21(s,1H,CH),9.12–9.05(m,1H,CH),8.82(ddt,J=15.7,5.1,1.5Hz,1H,CH),8.64(d,J=2.3Hz,1H,CH),8.28(d d,J=8.0,2.2Hz,1H,CH),7.84–7.72(m,2H,2*CH),7.62–7.52(m,1H,CH),7.2 3–7.16(m,1H,CH),7.18(s,1H,CH),4.74–4.59(m,2H,CH2),1.87(s,3H,CH3). LRMS(+ESI)496.1m / z:[(M+H)+,100%].

[0386] Example 14 Preparation of (S)-1-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-3-(4-cyanophenoxy)-2-methyl-1-oxopropan-2-yl 3-(dimethylamino)propanoate

[0387] Under nitrogen protection and in an ice bath, (S)-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropionamide (0.1 mmol), triethylamine (0.2 mmol), and 2,4,6-trichlorobenzoyl chloride (0.2 mmol) were added to toluene (2 mL) and stirred to dissolve. 4-Dimethylaminopyridine (0.4 mmol) and 3-dimethylaminopropane hydrochloride (0.4 mmol) were then added to the solution, the temperature was controlled below 0°C, and the reaction was stirred for 30 minutes. TLC showed that the reaction was complete, and the reaction solution was added to saturated sodium bicarbonate aqueous solution to quench it and extracted with ethyl acetate. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The crude product was obtained after distillation under reduced pressure, and the target compound was obtained after separation by chromatographic column. It was a white powdery solid with a yield of 3%.

[0388] LRMS(+ESI)490.2m / z:[(M+H)+,100%].

[0389] Example 15 Preparation of (S)-1-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-3-(4-cyanophenoxy)-2-methyl-1-oxopropan-2-yl 5-((R)-1,2-dithiolan-3-yl)pentanoate

[0390] Under nitrogen protection and in an ice bath, (S)-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropionamide (0.8 mmol), triethylamine (1.9 mmol), and 2,4,6-trichlorobenzoyl chloride (1.9 mmol) were added to toluene (10 mL) and stirred to dissolve. 4-Dimethylaminopyridine (3.8 mmol) and R-(+)-lipoic acid (1.6 mmol) were then added to the solution. The temperature was controlled below 0°C and the reaction was stirred for 30 minutes. TLC indicated the reaction was complete. The reaction solution was quenched by adding saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure and separated by column chromatography to obtain the target compound as a white powdery solid in a 35% yield.

[0391] 1H NMR (400MHz, DMSO-d6) δ10.77(s,1H,NH),9.23(d,J=2.3Hz,1H,CH),8.66(d,J=2.3Hz,1H,CH),7.85–7.68(m,2H,CH2),7.24–7.07(m ,2H,CH2),4.55(d,J=10.6Hz,1H,1 / 2*CH2),4.48(d,J=10.5Hz,1H,1 / 2*CH2),3.48(dq,J=8.8,6.2Hz,1H,CH),3.18–2.99(m,2H,CH2) ,2.42(td,J=7.1,2.1Hz,2H,CH2),2.32(dtd,J=12.9,6.5,5.6Hz,1H,1 / 2*CH),1.77(dd,J=12.8,6.7Hz,1H,1 / 2*CH),1.72(s,3H,CH3 ),1.59(ddd,J=13.8,8.2,4.4Hz,1H,1 / 2*CH),1.52–1.40(m,1H,1 / 2*CH),1.37–1.23(m,3H,CH,CH2).1.22(d,J=6.2Hz,1H,1 / 2*CH). LRMS(+ESI)579.2m / z:[(M+H)+,100%].

[0392] Example 16 Preparation of (S)-1-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-3-((6-cyanopyridin-3-yl)oxy)-2-methyl-1-oxopropan-2-yl 5-((R)-1,2-dithiolan-3-yl)pentanoate

[0393] Under nitrogen protection and in an ice bath, (S)-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-3-((6-cyanopyridin-3-yl)oxy)-2-hydroxy-2-methylpropionamide (0.8 mmol), triethylamine (1.9 mmol), and 2,4,6-trichlorobenzoyl chloride (1.9 mmol) were added to toluene (10 mL) and stirred to dissolve. 4-Dimethylaminopyridine (3.8 mmol) and R-(+)-lipoic acid (1.6 mmol) were then added to the solution. The temperature was controlled below 0°C and the reaction was stirred for 30 minutes. TLC indicated the reaction was complete. The reaction solution was quenched by adding saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure and separated by column chromatography to obtain the target compound as a white powdery solid in a 21% yield.

[0394] 1H NMR (400MHz, DMSO-d6) δ10.76(s,1H,NH),9.22(d,J=2.3Hz,1H,CH),8.65(d,J=2.3Hz,1H,CH),8.52–8.41(m, 1H,CH),8.00(d,J=0.6Hz,1H,CH),7.67(dd,J=8.7,2.9Hz,1H,CH),4.66–4.55(m,2H,CH2),3.49(dq,J=8.8,6 .2Hz,1H,CH),3.18–3.00(m,2H,CH2),2.42(t,J=7.1Hz,2H,CH2),2.32(dq,J=12.5,6.3Hz,1H,1 / 2*CH2),1.8 4–1.74(m,1H,1 / 2*CH2),1.73(s,3H,1 / 2*CH2,CH2),1.70–1.40(m,3H,1 / 2*CH2,CH2),1.36–1.23(m,3H,CH3). LRMS(+ESI)578.0m / z:[(M+H)+,100%].

[0395] Example 17 Preparation of (S)-1-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-3-(4-cyanophenoxy)-2-methyl-1-oxopropan-2-ylpropane-1-sulfonate

[0396] Under the protection of nitrogen, in an ice bath, (S)-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropionamide (0.8 mmol), triethylamine (1.9 mmol) and 2,4,6-trichlorobenzoyl chloride (1.9 mmol) were added to toluene (10 mL) and stirred to dissolve. Subsequently, 4-dimethylaminopyridine (3.8 mmol) and propylsulfonyl chloride (1.6 mmol) were added to the solution, the temperature was controlled below 0°C, and the reaction was stirred for 30 minutes. TLC showed that the reaction was complete, and the reaction solution was added to saturated sodium bicarbonate aqueous solution to quench it and extracted with ethyl acetate. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The crude product was obtained after distillation under reduced pressure, and the above-mentioned target compound was obtained after separation by chromatographic column. Pale yellow oil droplets, yield 5%.

[0397] LRMS(+ESI)497.0m / z:[(M+H)+,100%].

[0398] Example 18 Preparation of (S)-1-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-3-((6-cyanopyridin-3-yl)oxy)-2-methyl-1-oxopropan-2-ylpropane-1-sulfonate

[0399] Under the protection of nitrogen, in an ice bath, (S)-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-3-((6-cyanopyridin-3-yl)oxy)-2-hydroxy-2-methylpropionamide (0.8 mmol), triethylamine (1.9 mmol) and 2,4,6-trichlorobenzoyl chloride (1.9 mmol) were added to toluene (10 mL) and stirred to dissolve. 4-Dimethylaminopyridine (3.8 mmol) and propylsulfonyl chloride (1.6 mmol) were then added to the solution, the temperature was controlled below 0°C, and the reaction was stirred for 30 minutes. TLC showed that the reaction was complete, and the reaction solution was added to a saturated aqueous sodium bicarbonate solution to quench it, and ethyl acetate was added for extraction. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure and separated by column chromatography to yield the target compound (S)-1-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-3-((6-cyanopyridin-3-yl)oxy)-2-methyl-1-oxopropan-2-ylpropane-1-sulfonate. The product was a pale yellow oil in a 7% yield.

[0400] LRMS(-ESI)496.0m / z:[(MH)-,100%].

[0401] Example 19 Preparation of (S)-1-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-3-(4-cyanophenoxy)-2-methyl-1-oxopropan-2-yl 1-methylpiperidine-4-carboxylate

[0402] Under the protection of nitrogen, in an ice bath, (S)-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropionamide (0.8 mmol), triethylamine (1.9 mmol) and 2,4,6-trichlorobenzoyl chloride (1.9 mmol) were added to toluene (10 mL) and stirred to dissolve. Subsequently, 4-dimethylaminopyridine (3.8 mmol) and 1-methylpiperidine-4-carboxylic acid (1.6 mmol) were added to the solution, the temperature was controlled below 0°C, and the reaction was stirred for 30 minutes. TLC showed that the reaction was complete, and the reaction solution was added to a saturated aqueous sodium bicarbonate solution to quench it, and ethyl acetate was added for extraction. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure and separated by column chromatography to yield the target compound (S)-1-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-3-(4-cyanophenoxy)-2-methyl-1-oxopropan-2-yl 1-methylpiperidine-4-carboxylate as a pale yellow powdery solid in a 15% yield.

[0403] 1 H NMR (400MHz, DMSO-d6) δ10.88(s,1H,NH),9.40(d,J=2.3Hz,1H,CH),8.89(d,J=2.3Hz, 1H,CH),7.75(m,2H,2*CH),7.19–7.03(m,2H,2*CH),4.32(d,J=10.0Hz,1H,1 / 2*CH2), 4.09(d,J=10.0Hz,1H,1 / 2*CH2),2.68(d,J=15.1Hz,2H,CH2),2.19–2.10(m,3H,CH3), 1.95(s,2H,CH2),1.77(d,J=8.9Hz,2H,CH2),1.61–1.47(m,2H,CH2),1.44(s,3H,CH3). LRMS(+ESI)516.2m / z:[(M+H)+,100%].

[0404] Example 20 Preparation of (S)-1-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-3-((6-cyanopyridin-3-yl)oxy)-2-methyl-1-oxopropan-2-yl 1-methylpiperidine-4-carboxylate

[0405] Under the protection of nitrogen, in an ice bath, (S)-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-3-((6-cyanopyridin-3-yl)oxy)-2-hydroxy-2-methylpropionamide (0.8 mmol), triethylamine (1.9 mmol) and 2,4,6-trichlorobenzoyl chloride (1.9 mmol) were added to toluene (10 mL) and stirred to dissolve. Subsequently, 4-dimethylaminopyridine (3.8 mmol) and 1-methylpiperidine-4-carboxylic acid (1.6 mmol) were added to the solution, the temperature was controlled below 0°C, and the reaction was stirred for 30 minutes. TLC showed that the reaction was complete, and the reaction solution was added to a saturated aqueous sodium bicarbonate solution to quench it, and ethyl acetate was added for extraction. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure and separated by column chromatography to yield the target compound (S)-1-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-3-((6-cyanopyridin-3-yl)oxy)-2-methyl-1-oxopropan-2-yl 1-methylpiperidine-4-carboxylate as a pale yellow powdery solid in a 10% yield.

[0406] LRMS(+ESI)517.1m / z:[(M+H)+,100%].

[0407] Example 21 Preparation of (S)-1-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-3-(4-cyanophenoxy)-2-methyl-1-oxopropan-2-yl isobutyrate

[0408] Under the protection of nitrogen, in an ice bath, (S)-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropionamide (0.8 mmol), triethylamine (1.9 mmol) and 2,4,6-trichlorobenzoyl chloride (1.9 mmol) were added to toluene (10 mL) and stirred to dissolve. 4-Dimethylaminopyridine (3.8 mmol) and isobutyric acid (1.6 mmol) were then added to the solution, the temperature was controlled below 0°C, and the reaction was stirred for 30 minutes. TLC showed that the reaction was complete, and the reaction solution was added to a saturated aqueous sodium bicarbonate solution to quench it, and ethyl acetate was added for extraction. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure and separated by column chromatography to yield the target compound (S)-1-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-3-(4-cyanophenoxy)-2-methyl-1-oxopropan-2-yl isobutyrate as a white powdery solid in a 25% yield.

[0409] 1H NMR (500MHz, DMSO-d6) δ10.70(s,1H,NH),9.24(d,J=2.3Hz,1H,CH),8.68(d,J=2.3Hz,1H,CH),7.82–7.75(m,2H,2*CH),7.17(d,J =8.4Hz,2H,2*CH),4.57(d,J=10.4Hz,1H,1 / 2*CH2),4.51(d,J=10.5Hz,1H,1 / 2*CH2),1.74(s,3H,CH3),1.11–1.05(m,6H,2*CH3). LRMS(+ESI)461.1m / z:[(M+H)+,100%], LRMS(-ESI)459.1m / z:[(MH)-,100%].

[0410] Example 22 Preparation of (S)-1-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-3-(4-cyanophenoxy)-2-methyl-1-oxopropan-2-ylcyclopentanecarboxylate

[0411] Under the protection of nitrogen, in an ice bath, (S)-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropionamide (0.8 mmol), triethylamine (1.9 mmol) and 2,4,6-trichlorobenzoyl chloride (1.9 mmol) were added to toluene (10 mL) and stirred to dissolve. 4-Dimethylaminopyridine (3.8 mmol) and cyclopentanecarboxylic acid (1.6 mmol) were then added to the solution, the temperature was controlled below 0°C, and the reaction was stirred for 30 minutes. TLC showed that the reaction was complete, and the reaction solution was added to a saturated aqueous sodium bicarbonate solution to quench it, and ethyl acetate was added for extraction. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure and separated by column chromatography to yield the target compound (S)-1-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-3-(4-cyanophenoxy)-2-methyl-1-oxopropan-2-ylcyclopentanecarboxylate as a white powdery solid in a 28% yield.

[0412] 1H NMR (500MHz, DMSO-d6) δ10.71 (s, 1H, NH), 9.23 (d, J = 2.3Hz, 1H, CH), 8.68 (d, J = 2. 3Hz,1H,CH),7.82–7.75(m,2H,CH2),7.20–7.14(m,2H,CH2),4.57(d,J=10.5Hz,1H ,1 / 2*CH2),4.50(d,J=10.5Hz,1H,1 / 2*CH2),1.89–1.79(m,2H,CH2),1.74(s,3H, CH3), 1.67 (ddt, J=11.5, 7.3, 3.8Hz, 2H, CH2), 1.53 (tt, J=7.5, 3.3Hz, 4H, 2*CH2). LRMS(+ESI)487.1m / z:[(M+H)+,100%], LRMS(-ESI)485.1m / z:[(MH)-,100%].

[0413] Example 23 Preparation of (S)-1-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-3-(4-cyanophenoxy)-2-methyl-1-oxopropan-2-yl N-methyl-L-proline

[0414] Under the protection of nitrogen, in an ice bath, (S)-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropionamide (0.8 mmol), triethylamine (1.9 mmol) and 2,4,6-trichlorobenzoyl chloride (1.9 mmol) were added to toluene (10 mL) and stirred to dissolve. Subsequently, 4-dimethylaminopyridine (3.8 mmol) and N-methyl-L-proline (1.6 mmol) were added to the solution, the temperature was controlled below 0°C, and the reaction was stirred for 30 minutes. TLC showed that the reaction was complete, and the reaction solution was added to a saturated aqueous sodium bicarbonate solution to quench it, and ethyl acetate was added for extraction. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure and separated by column chromatography to yield the target compound (S)-1-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-3-(4-cyanophenoxy)-2-methyl-1-oxopropan-2-yl, N-methyl-L-proline, as a white powdery solid in a 36% yield.

[0415] 1H NMR (500MHz, DMSO-d6) δ10.75(s,1H,NH),9.22(s,1H,CH),8.69(s,1H,CH),7.79(d,J=8.5Hz,2H,2*CH),7.17(d ,J=8.3Hz,2H,2*CH),4.60(d,J=10.5Hz,1H,1 / 2*CH2),4.52(d,J=10.4Hz,1H,1 / 2*CH2),3.13(t,J=7.5Hz,1H,1 / 2*CH2), 2.95–2.87 (m, 1H, 1 / 2*CH2), 2.29 (s, 3H, CH3), 2.07 (dt, J = 17.0, 8.7 Hz, 1H, 1 / 2*CH2), 1.83 (dq, J = 11.9, 5.7 Hz, 1H, 1 / 2*CH2), 1.77 (s, 3H, CH3), 1.72 (dd, J = 8.4, 3.8 Hz, 1H, 1 / 2*CH2), 1.68 (d, J = 9.0 Hz, 1H, 1 / 2*CH2). LRMS (+ESI) 502.2 m / z: [(M+H)+, 100%], LRMS (-ESI) 500.1 m / z: [(MH)-, 100%].

[0416] Example 24 Preparation of (S)-1-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-3-(4-cyanophenoxy)-2-methyl-1-oxopropan-2-yl acetate (SARM-46)

[0417] Under nitrogen, (S)-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamide (0.3 mmol), 4-dimethylaminopyridine (0.4 mmol), and acetic anhydride (0.6 mmol) were added to 5 mL of pyridine and stirred to dissolve. The temperature was controlled between 80°C and 85°C, and the reaction was stirred for 3 hours. TLC indicated the reaction was complete. The reaction solution was added to water and extracted with 20 mL of ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure and separated by column chromatography to yield the target compound, (S)-1-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-3-(4-cyanophenoxy)-2-methyl-1-oxopropan-2-yl acetate. The product was obtained as a white powdery solid in a 77% yield.

[0418] 1H NMR (400MHz, DMSO-d6) δ10.76(s,1H,NH),9.23(d,J=2.3Hz,1H,CH),8.65(d,J=2.3Hz,1H,CH),7.85–7.7 0(m,2H,2*CH),7.24–7.07(m,2H,2*CH),4.49(h,J=9.5Hz,2H,CH2),2.11(s,3H,CH3),1.71(s,3H,CH3). LRMS(-ESI)431.0m / z:[(MH)-,100%].

[0419] Example 25 Preparation of (S)-1-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-3-((6-cyanopyridin-3-yl)oxy)-2-methyl-1-oxopropan-2-yl acetate

[0420] Under nitrogen, (S)-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-3-((6-cyanopyridin-3-yl)oxy)-2-hydroxy-2-methylpropanamide (0.3 mmol), 4-dimethylaminopyridine (0.4 mmol), and acetic anhydride (0.6 mmol) were added to 5 mL of pyridine and stirred to dissolve. The temperature was controlled between 80°C and 85°C, and the reaction was stirred for 3 hours. TLC indicated the reaction was complete. The reaction solution was added to water and extracted with 20 mL of ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure and separated by column chromatography to obtain the target compound (S)-1-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-3-((6-cyanopyridin-3-yl)oxy)-2-methyl-1-oxopropan-2-yl acetate. The product was obtained as a white powdery solid in a 90% yield.

[0421] 1 H NMR (400MHz, DMSO-d6) δ10.78(s,1H,CH),9.24(d,J=2.2Hz,1H,CH),8.65(d,J=2.3Hz,1H,CH),8.49(dd,J=2.9,0.6Hz,1H,CH) ,8.01(dd,J=8.7,0.6Hz,1H,CH),7.67(dd,J=8.7,2.9Hz,1H,CH),4.65–4.53(m,2H,CH2),2.11(s,3H,CH3),1.72(s,3H,CH3). LRMS(-ESI)432.0m / z:[(MH)-,100%].

[0422] Example 26 Preparation of (S)-1-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-3-(4-cyanophenoxy)-2-methyl-1-oxopropan-2-ylbenzoate

[0423] Under nitrogen, (S)-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropionamide (0.3 mmol), 4-dimethylaminopyridine (0.4 mmol), and benzoic anhydride (0.6 mmol) were added to 5 mL of pyridine and stirred to dissolve. The temperature was controlled between 80°C and 85°C, and the reaction was stirred for 3 hours. TLC indicated the reaction was complete. The reaction solution was added to water and extracted with 20 mL of ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure and separated by column chromatography to yield the target compound, (S)-1-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-3-(4-cyanophenoxy)-2-methyl-1-oxopropan-2-yl benzoate. The product was obtained as a white powdery solid in a yield of 78%.

[0424] 1 H NMR (400MHz, DMSO-d6) δ10.85 (s, 1H, NH), 9.23 (d, J = 2.3Hz, 1H, CH), 8.66 (d, J = 2. 3Hz,1H,CH),8.03–7.87(m,2H,2*CH),7.84–7.73(m,1H,CH),7.73(d,J=15.3Hz,1H ,CH),7.72–7.57(m,1H,CH),7.57–7.44(m,2H,2*CH),7.19(d,J=6.9Hz,1H,CH),4. 69(d,J=10.8Hz,1H,1 / 2*CH2), 4.63(d,J=10.8Hz,1H,1 / 2*CH2), 1.85(s,3H,CH3). LRMS(-ESI)493.0m / z:[(MH)-,100%].

[0425] Example 27 Preparation of (S)-1-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-3-((6-cyanopyridin-3-yl)oxy)-2-methyl-1-oxopropan-2-ylbenzoate

[0426] Under nitrogen, (S)-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-3-((6-cyanopyridin-3-yl)oxy)-2-hydroxy-2-methylpropanamide (0.3 mmol), 4-dimethylaminopyridine (0.4 mmol), and benzoic anhydride (0.6 mmol) were added to 5 mL of pyridine and stirred to dissolve. The temperature was controlled between 80°C and 85°C, and the reaction was stirred for 3 hours. TLC indicated the reaction was complete. The reaction solution was added to water and extracted with 20 mL of ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure and separated by column chromatography to yield the target compound, (S)-1-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-3-((6-cyanopyridin-3-yl)oxy)-2-methyl-1-oxopropan-2-yl benzoate. White powdery solid, yield 91%.

[0427] 1 H NMR (400MHz, DMSO-d6) δ10.86(s,1H,NH),9.24(s,1H,CH),8.65(s,1H,CH),8.51(d,J=2.8Hz,1H,CH),8.01(d,J=8.7Hz,1H,CH ),7.94(d,J=7.6Hz,2H,2*CH),7.76–7.65(m,2H,2*CH),7.53(t,J=7.7Hz,2H,2*CH),4.81–4.69(m,2H,CH2),1.86(s,3H,CH3). LRMS(-ESI)494.0m / z:[(MH)-,100%].

[0428] Example 28 Preparation of (S)-1-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-3-(4-cyanophenoxy)-2-methyl-1-oxopropan-2-ylpropanoate

[0429] Under nitrogen, (S)-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropionamide (0.3 mmol), 4-dimethylaminopyridine (0.4 mmol), and propionic anhydride (0.6 mmol) were added to 5 mL of pyridine and stirred to dissolve. The temperature was controlled between 80°C and 85°C, and the reaction was stirred for 3 hours. TLC indicated the reaction was complete. The reaction solution was added to water and extracted with 20 mL of ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure and separated by column chromatography to yield the target compound, (S)-1-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-3-(4-cyanophenoxy)-2-methyl-1-oxopropan-2-yl propionate. The product was obtained as a white powdery solid in a 95% yield.

[0430] 1 H NMR(500MHz,DMSO-d6)δ10.74(s,1H,NH),9.25(d, J=2.2Hz,1H,CH),8.68(d,J=2.3Hz,1H,CH),7.81–7.76(m,2H,2*CH),7.21–7.14(m,2H,2*CH),4.58–4.53(m,1H,1 / 2*CH2),4.50 (dd,J=10.5,1.9Hz,1H,1 / 2*CH2),2.45(qd,J=7.5,1.8Hz,2H,CH2),1.74(d,J=2.0Hz,3H,CH3),1.01(td,J=7.5,1.9Hz,3H,CH3). LRMS(+ESI)447.1m / z:[(M+H)+,100%], LRMS(-ESI)445.1m / z:[(MH)-,100%].

[0431] Example 29 Preparation of (S)-1-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-3-(4-chlorophenoxy)-2-methyl-1-oxopropan-2-yl nicotinate

[0432] Under nitrogen, (S)-3-(4-chlorophenoxy)-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-2-hydroxy-2-methylpropionamide (0.3 mmol), 4-dimethylaminopyridine (0.4 mmol), and nicotinic anhydride (0.6 mmol) were added to 5 mL of pyridine and stirred to dissolve. The temperature was controlled between 80°C and 85°C, and the reaction was stirred for 3 hours. TLC indicated the reaction was complete. The reaction solution was added to water and extracted with 20 mL of ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure and separated by column chromatography to yield the target compound, (S)-1-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-3-(4-chlorophenoxy)-2-methyl-1-oxopropan-2-yl nicotinate. The product was obtained as a white powdery solid in a 91% yield.

[0433] 1 H NMR(500MHz,DMSO-d6)δ10.83(s,1H,NH),9.24(s,1H,CH),9.12(d,J=2.2Hz,1H,CH),8. 86(dt,J=4.8,1.5Hz,1H,CH),8.66(d,J=2.4Hz,1H,CH),8.29(dq,J=8.1,1.8Hz,1H,CH), 7.60(dd,J=8.0,4.9Hz,1H,CH),7.36–7.29(m,2H,2*CH),7.09–7.02(m,2H,2*CH),4.62( d, J=10.7Hz, 1H, 1 / 2*CH2), 4.57 (d, J=10.8Hz, 1H, 1 / 2*CH2), 1.88 (d, J=1.3Hz, 3H, CH3). LRMS(-ESI)m / z:503.1 / 504.1 / 505.1,[(MH)-,100 / 30% / 33%].

[0434] Example 30 Preparation of (S)-1-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-3-((6-chloropyridin-3-yl)oxy)-2-methyl-1-oxopropan-2-ylnicotinate

[0435] Under nitrogen, (S)-3-((6-chloropyridin-3-yl)oxy)-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-2-hydroxy-2-methylpropanamide (0.3 mmol), 4-dimethylaminopyridine (0.4 mmol), and nicotinic anhydride (0.6 mmol) were added to 5 mL of pyridine and stirred to dissolve. The temperature was controlled between 80°C and 85°C, and the reaction was stirred for 3 hours. TLC indicated the reaction was complete. The reaction solution was added to water and extracted with 20 mL of ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure and separated by column chromatography to yield the target compound, (S)-1-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-3-((6-chloropyridin-3-yl)oxy)-2-methyl-1-oxopropan-2-yl nicotinate. The product was obtained as a white powdery solid in a 91% yield.

[0436] 1 H NMR (500MHz, DMSO-d6) δ10.85(s,1H,NH),9.25(d,J=2.0Hz,1H,CH),9.12(dd,J=2.2,0.8Hz,1H,CH),8.87(dd,J=4.8,1.7Hz,1H,CH),8.66(d,J=2.3Hz,1H,C H),8.30(dt,J=8.0,2.0Hz,1H,CH),8.22(d,J=3.1Hz,1H,CH),7.64–7.58(m,2 H,2*CH),7.44(d,J=8.8Hz,1H,CH),4.74–4.65(m,2H,CH2),1.89(s,3H,CH3). LRMS(-ESI)m / z:506.1 / 507.1 / 508.1,[(MH)-,100 / 20% / 33%].

[0437] Example 31 Preparation of (S)-3-(4-cyano-3-fluorophenoxy)-1-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-2-methyl-1-oxopropan-2-ylnicotinate

[0438] Under nitrogen, (S)-3-(4-cyano-3-fluorophenoxy)-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-2-hydroxy-2-methylpropionamide (0.3 mmol), 4-dimethylaminopyridine (0.4 mmol), and nicotinic anhydride (0.6 mmol) were added to 5 mL of pyridine and stirred to dissolve. The temperature was controlled between 80°C and 85°C, and the reaction was stirred for 3 hours. TLC indicated the reaction was complete. The reaction solution was added to water and extracted with 20 mL of ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure and separated by column chromatography to yield the target compound, (S)-3-(4-cyano-3-fluorophenoxy)-1-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-2-methyl-1-oxopropan-2-yl nicotinate. The product was obtained as a white powdery solid in an 88% yield.

[0439] LRMS(-ESI)512.0m / z:[(MH)-,100%].

[0440] Example 32 Preparation of (S)-3-(4-cyano-3-fluorophenoxy)-1-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-2-methyl-1-oxopropan-2-yl acetate

[0441] Under nitrogen, (S)-3-(4-cyano-3-fluorophenoxy)-N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-2-hydroxy-2-methylpropanamide (0.3 mmol), 4-dimethylaminopyridine (0.4 mmol), and acetic anhydride (0.6 mmol) were added to 5 mL of pyridine and stirred to dissolve. The temperature was controlled between 80°C and 85°C, and the reaction was stirred for 3 hours. TLC indicated the reaction was complete. The reaction solution was added to water and extracted with 20 mL of ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure and separated by column chromatography to obtain the target compound (S)-3-(4-cyano-3-fluorophenoxy)-1-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-2-methyl-1-oxopropan-2-yl acetate. The product was obtained as a white powdery solid in an 80% yield.

[0442] LRMS(-ESI)449.1m / z:[(MH)-,100%].

[0443] Example 33 Preparation of (S)-3-(((1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-3-(4-cyanophenoxy)-2-methyl-1-oxopropan-2-yl)oxy)carbonyl)-1-methylpyridine-1-trifluoromethanesulfonate

[0444] Under inert gas, (S)-1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-3-(4-cyanophenoxy)-2-methyl-1-oxopropan-2-ylnicotinate (0.2 mmol) and methyl trifluoromethanesulfonate (0.3 mmol) were added to DCM and stirred at room temperature for 3 hours. TLC indicated the reaction was complete. 5 mL of ether was added, the mixture was stirred, and then filtered. The filter cake was washed with 10 mL of ether and dried to obtain the target compound (S)-3-(((1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-3-(4-cyanophenoxy)-2-methyl-1-oxopropan-2-yl)oxy)carbonyl)-1-methylpyridinium-1-trifluoromethanesulfonate as a white powdery solid in an 85% yield.

[0445] 1 H NMR (400MHz, DMSO-d6) δ10.60(s,1H,NH),9.56(s,1H,CH),9.20(d,J=6.1Hz,1H,CH),8.99(d,J=8.1Hz,1H,CH),8.28(dd,J=8.1,6.1Hz,1H,CH),8.22( s,1H,CH),8.13(d,J=1.2Hz,2H,2*CH),7.86–7.70(m,2H,2*CH),7.27–7.10 (m,2H,2*CH),4.75–4.63(m,2H,2*CH),4.41(s,3H,CH3),1.92(s,3H,CH3). LRMS(-ESI)509.0m / z:[(MH)-,100%].

[0446] Example 34 Preparation of (S)-3-(((1-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-3-(4-cyanophenoxy)-2-methyl-1-oxopropan-2-yl)oxy)carbonyl)-1-methylpyridine-1-trifluoromethanesulfonate

[0447] Under inert gas, (S)-1-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-3-(4-cyanophenoxy)-2-methyl-1-oxopropan-2-yl nicotinate (0.2 mmol) and methyl trifluoromethanesulfonate (0.3 mmol) were added to DCM and stirred at room temperature for 3 hours. TLC indicated the reaction was complete. 5 mL of ether was added, stirred, and filtered. The filter cake was washed with 10 mL of ether and dried to obtain the title compound as a white powdery solid in a 60% yield.

[0448] 1H NMR(500MHz,DMSO-d6)δ10.89(s,1H,NH),9.60(d,J=11.1Hz,1H,CH),9.28–9.21(m,2H,2*CH),9.03(t,J=7.7Hz,1H,CH),8.32(ddd,J=11.6,8.0,6.0H z,1H,CH),7.82(dd,J=15.0,8.7Hz,2H,2*CH),7.24–7.17(m,2H,2*CH),4.74–4.67(m,2H,CH2),4.44(d,J=9.0Hz,3H,CH3),1.96(d,J=5.3Hz,3H,CH3). LRMS(+ESI)510.1 / 511.1m / z:[(M+H)+,100 / 33%].

[0449] Example 35 Preparation of (S)-1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-3-(4-cyanophenoxy)-2-methyl-1-oxopropan-2-yl 1-methyl-1,4-dihydropyridine-3-carboxylate

[0450] Under nitrogen, (S)-3-(((1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-3-(4-cyanophenoxy)-2-methyl-1-oxopropan-2-yl)oxy)carbonyl)-1-methylpyridine-1-trifluoromethanesulfonate (0.1 mmol) and 1-benzyl-1,4-dihydronicotinamide (0.1 mmol) were added to DCM, and the reaction was stirred at room temperature overnight. TLC indicated the reaction was complete, and the reaction solution was added to 10 mL of water and extracted with 20 mL of ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure and separated by column chromatography to yield the target compound (S)-1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-3-(4-cyanophenoxy)-2-methyl-1-oxopropan-2-yl-1-methyl-1,4-dihydropyridine-3-carboxylate. The product was a yellow powdery solid in a 91% yield.

[0451] 1H NMR(400MHz,DMSO-d6)δ10.33(s,1H,NH),8.30(d,J=2.0Hz,1H,CH),8.18–8.11(m,1H,CH),8.1 1–8.02(m,2H,2*CH),7.85–7.69(m,2H,2*CH),7.15(d,J=8.8Hz,2H,2*CH),7.03(d,J=1.6Hz,1H ,CH),5.87–5.80(m,1H,CH),4.73(dt,J=7.7,3.5Hz,1H,CH),4.54(d,J=10.6Hz,1H,1 / 2*CH2),4 .45(d,J=10.6Hz,1H,1 / 2*CH2),2.92(s,3H,CH3),2.89(d,J=3.4Hz,2H,CH3),1.66(s,3H,CH3). LRMS(-ESI)510.0m / z:[(MH)-,100%].

[0452] Example 36 Preparation of (S)-1-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-3-(4-cyanophenoxy)-2-methyl-1-oxopropan-2-yl 1-methyl-1,4-dihydropyridine-3-carboxylate

[0453] Under nitrogen, (S)-3-(((1-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-3-(4-cyanophenoxy)-2-methyl-1-oxopropan-2-yl)oxy)carbonyl)-1-methylpyridine-1-trifluoromethanesulfonate (0.1 mmol) and 1-benzyl-1,4-dihydronicotinamide (0.1 mmol) were added to DCM, and the reaction was stirred at room temperature overnight. TLC indicated the reaction was complete, and the reaction solution was added to 10 mL of water and extracted with 20 mL of ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The crude product was distilled under reduced pressure and separated by column chromatography to yield the target compound (S)-1-((6-cyano-5-(trifluoromethyl)pyridin-3-yl)amino)-3-(4-cyanophenoxy)-2-methyl-1-oxopropan-2-yl 1-methyl-1,4-dihydropyridine-3-carboxylate. The product was a yellow powdery solid in a 75% yield.

[0454] LRMS(+ESI)512.1m / z:[(M+H)+,100%], LRMS(-ESI)510.1 / 511.1m / z:[(MH)-,100 / 30%].

[0455] II. Formulation Examples

[0456] Formulation Example A: Preparation of Injection

[0457] (1) Batch formula composition:

[0458] (2) Preparation method:

[0459] According to the formula, the compound of Example 19, polysorbate 80, and mannitol were added to 4000 ml of water for injection. After stirring to dissolve, water for injection was added to a total volume of 5000 ml. Stirring was continued, and the mixture was sterile filtered through a 0.22 μm microporous filter membrane. The filtrate was aseptically filled into 5 ml ampoules (specification: 20 mg / ampoule) at a rate of 5 ml per vial, sealed, and sterilized.

[0460] Formulation Example B: Preparation of Tablets

[0461] (1) Formula composition (dosage per 1000 tablets)

[0462] (2) Preparation process

[0463] The compound of Example 19, lactose, and part of the microcrystalline cellulose were micronized in a ratio of 200:100:40. The remaining microcrystalline cellulose, lactose, pregelatinized starch, micropowdered silica gel, and sodium carboxymethyl starch that had passed through an 80-mesh sieve were added according to the formula ratio and mixed evenly. An appropriate amount of 0.3% HPMC solution was added to prepare a soft material. The mixture was granulated with an 18-mesh sieve and dried at 60°C (the moisture content of the granules was controlled at approximately 3%). Magnesium stearate that had passed through an 80-mesh sieve was added and mixed evenly with the granules. The granules were sieved through a 16-mesh sieve, tableted, and packaged.

[0464] Formulation Example C: Preparation of Tablets

[0465] (1) Formula composition (dosage per 1000 tablets)

[0466] (2) Preparation process

[0467] Tablets of Formulation Example C were prepared similarly to Formulation Example B above.

[0468] Formulation Example D: Preparation of Tablets

[0469] (1) Formula composition (dosage per 1000 tablets)

[0470] (2) Preparation process

[0471] Tablets of Formulation Example D were prepared similarly to Formulation Example B above.

[0472] III. Bioactivity Assay

[0473] 1. Small molecule and protein affinity (protein ligand coupling) experiment

[0474] (1) Experimental equipment

[0475] Biacore TM T200by CM5 series chips (purchased from Catalog number: 29149604), human androgen receptor (AR) recombinant protein (CLOUD-CLONE CORP. WUHAN, RPB252Hu03, Ile673~His918 with N-terminal His Tag).

[0476] (2) Experimental process

[0477] 1) pH screening: Screen the appropriate ligand buffer pH from 10 mM sodium acetate at pH 5.5, 5.0, 4.5, and 4, with a ligand concentration of 10-100 μg / ml. Contact time = 180 s, flow rate = 5 μl / min, followed by surface regeneration with 50 mM NaOH.

[0478] 2) Ligand immobilization: Immobilize using amino-direct coupling. Activate and immobilize the ligand using EDC / NHS, then block with ethanolamine. Automated coupling is performed using the aim for immobilized level mode and a target level of 1000 RU. After coupling, the amount of coupling is measured using the response bound method.

[0479] 3) Surface Testing: Prepare 85 nM, 8.5 nM, and 0.85 nM β2-microglobulin solutions and glycine hydrochloride regeneration solution, respectively, and place them on the sample rack. Set the contact time to 180 seconds and the wait time to 60 seconds. Select the corresponding position for the regeneration solution and set the contact time to 30 seconds. Repeat the surface testing-regeneration process for the three samples. Use the sensorgram results of channel 2 subtracted from channel 1 to examine whether the analyte and ligand are bound, whether the injection dissociation time is appropriate, and estimate the KD value.

[0480] 4) Regeneration conditions: Glycine hydrochloride at different pH values ​​was used for regeneration. The regeneration solution flow rate was 30 μl / min.

[0481] 5) Set up a reasonable analyte concentration gradient based on previous experimental results and perform kinetic analysis. Select a kinetic / affinity calculation method. For kinetic analysis, the Rmax value should be less than 100 RU.

[0482] (3) Experimental results

[0483] The affinity test results of the compounds of the present invention as androgen receptor ligands to androgen receptor protein are shown in the table below, where Ostarine is a control compound:

[0484] Table 1. In vitro small molecule and protein affinity results of the compounds

[0485] Note: NT means not tested.

[0486] Under the experimental conditions, the compounds of Examples 3, 4, 5, 11, 15, 24, and 26 have strong affinity for the androgen receptor protein. In contrast, the control compound Ostarine shows no affinity for the androgen receptor protein.

[0487] 2. Androgen Receptor Reporter Gene Assay (AR Reporter Gene Assay)

[0488] 2.1 Experimental Overview

[0489] This experiment investigates the ability of the compounds of the present invention to stimulate androgen receptors. The positive control compound used in the experiment is dihydrotestosterone (DHT, MCE, HY-A0120). The experiment mainly includes: HEK293T cells (ATCC, CRL-3216) transfected with plasmids are inoculated into well plates containing dilutions of corresponding concentrations of compounds, and the cells are detected by CellTiter-Fluor TM The fluorescence values ​​corresponding to different compounds were measured using a cell viability reagent (Promega, G6081) and a britelite plus luciferase assay reagent (PerkinElmer, 6066769). The relative receptor agonist activity of the compounds of the present invention was calculated using the formula with DHT as a positive control. At the same time, the EC was calculated by fitting the % activity value and the logarithm of the compound concentration to a nonlinear regression. 50 .

[0490] 2.2 Experimental Procedure

[0491] (1) Compound preparation

[0492] All test compounds were serially diluted 10 times in DMSO at a ratio of 1:3 from 10 mM to a final concentration of 0.000508053 mM, and each concentration was repeated 3 times. The positive control, dihydrotestosterone, was serially diluted 10 times in DMSO at a ratio of 1:3 from 0.1 mM to a final concentration of 5.08053E -06 Prepare 1000× positive control (0.1 mM dihydrotestosterone) and 1000× vehicle control (100% DMSO).

[0493] (2) Experimental operation

[0494] 1) HEK293T cells were cultured according to ATCC recommendations and assayed during the exponential growth phase;

[0495] 2) Remove the culture medium from the flask;

[0496] 3) Rinse cells with PBS;

[0497] 4) Add TrypLE solution to the flask and allow the cells to detach. Wash the cells once with complete growth medium.

[0498] 5) Pellet and wash the cells twice with PBS to remove phenol red, and resuspend them in culture medium to an appropriate concentration;

[0499] 6) Only cells with viability greater than 90% were used for the assay;

[0500] 7) 6*10 6 HEK293T cells were seeded into 100 mm culture dishes;

[0501] 8) Incubate cells at 37°C, 5% CO2 for 16 hours;

[0502] 9) Transfect the plasmid into cells and culture at 37°C, 5% CO2 for 5-6 hours;

[0503] 10) Use Echo655 to transfer 25uL of compound dilution to a 384-well assay plate;

[0504] 11) HEK293T cells were seeded into a 384-well assay plate at 17,000 cells / well;

[0505] 12) Incubate cells at 37°C, 5% CO2 for 18-20 hours;

[0506] 13) Add 25uL CellTiter-Fluor to each well of the 384-well plate TM Cell viability reagent, and incubate cells at 37°C, 5% CO2 for 30 minutes;

[0507] 14) Read the values ​​using ex 380nm / em 510nm;

[0508] 15) Add 25 μL of britelite plus luciferase assay reagent to each well of a 384-well assay plate and record the luminescence value on an Envision plate reader.

[0509] (3) Data processing

[0510] Calculate EC according to the following formula 50 :

[0511] Y=Bottom+(Top-Bottom) / (1+10^((LogEC 50 -X)*Hillslope))

[0512] in:

[0513] X is the logarithm of the activator concentration; Y is the inhibition percentage; Bottom is the lowest platform value of the curve; Top is the highest platform value of the curve; Hillslope is the slope of the curve.

[0514] Calculate the % relative potency according to the following formula:

[0515] % relative efficacy = (Activated cmpd -Activated Ave_VC ) / (Activated Ave_PC -Activated Ave_VC )*100

[0516] in:

[0517] Activated cmpd : Average activation value of compound signal in the whole plate

[0518] Activated Ave_PC : Average activation value of positive control in the whole plate.

[0519] Activated Ave_VC : Average activation value of negative control in the whole plate.

[0520] 2.3 Experimental Results

[0521] The test results of androgen receptor agonist ability of the control compound and some of the example compounds are shown in Table 2 below.

[0522] Table 2. Test results of androgen receptor agonist ability of compounds

[0523] Under these experimental conditions, the compounds of Examples 3, 5, 8, 13, 15, and 24 exhibited excellent androgen receptor protein binding and agonist activity. The remaining compounds also demonstrated good binding and agonist activity. Among them, Example 15 achieved a maximum agonist efficiency (EMAX) of up to 113% of DHT, making it a full androgen receptor agonist. Compared to ostarine, a SARM compound currently in clinical trials, all of the above compounds, with the exception of Examples 1, 2, 4, and 11, demonstrated superior agonist efficacy.

[0524] In addition, the above results also confirm that the novel aryl propionamide ester compounds wherein Ring A is a pyridine ring have significantly improved androgen receptor agonist efficacy compared to the corresponding aryl propionamide ester compounds wherein Ring A is a benzene ring, as shown below (wherein the KD results can be seen in Table 1 above):

[0525] At the same time, compared with the aryl propionamide ester compounds that retain free hydroxyl groups (i.e., L is a bond and R is hydrogen in Formula I), further modification of the hydroxyl groups can make the compounds maintain relatively excellent agonist efficacy (EC 50 <20 nM, the maximum agonist effect on androgen receptor was further improved as shown below (where E MAX The results can be seen in Table 2 above):

[0526] 3. Mouse Blood-Brain Barrier Permeability Experiment

[0527] 3.1 Animal Experimental Protocol and Procedure:

[0528] (1) The experimental protocol was based on and complies with the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health and was approved by the Laboratory Animal Welfare and Ethics Committee of the Chinese Institute for Brain Research (CIBR).

[0529] (2) Wild-type male C57BL / 6J mice aged 6-7 weeks and weighing 18-22 grams were used. The mice were housed in an incubator with a 12-hour light-dark cycle and had free access to food and water. Food was stopped the day before the experiment, and free drinking water was allowed. The mice were injected intraperitoneally with the test compound once at a dose of 20 mg / kg. The mice (3 mice per time point) were decapitated and bled at each of the following time points: 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 8 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, and 72 hours, and brain tissue and blood were collected.

[0530] (3) When collecting serum, use sodium heparin tubes. After sampling, centrifuge quickly at low speed to remove blood cells and minimize hemolysis. After collecting serum, send it to the mass spectrometry center for pre-processing.

[0531] (4) After processing, the brain tissue was quickly removed and frozen in liquid nitrogen for later use.

[0532] 3.2 Mass spectrometry analysis experimental process:

[0533] (1) Serum treatment

[0534] The sample (100uL) was heated to room temperature, acetonitrile:methanol (500uL, v / v=50:50) was added and the sample was vortexed for 20 seconds. The sample was centrifuged at 5,000g for 15 minutes at 4°C. Subsequently, 90% of the supernatant was transferred to a glass test tube and concentrated at 45°C for 1.5 hours using a vacuum concentrator. The dried sample was dissolved in 400uL of acetonitrile:water mixed solution (v / v=50 / 50) and vortexed for 20 seconds. The resulting mixture was transferred to an EP tube and centrifuged at 5,000g for 15 minutes at 4°C. The supernatant was filtered with a 0.22uM filter and analyzed by LC-MS / MS.

[0535] (2) Brain sample processing

[0536] Brain samples (100 mg) were thawed and transferred to a homogenizer tube containing 3 zircons, homogenized, and processed in the same manner as the serum treatment described above. The supernatant was filtered through a 0.22 uM filter and analyzed by LC-MS / MS.

[0537] 3.3 Experimental Results and Discussion

[0538] The concentrations of some of the example compounds in serum and brain after administration over time are shown in Figures 1 to 34 .

[0539] Metabolites were detected after administration of the compounds of Examples 13, 15, 21, 22, 24, 26, and 28. High-resolution mass spectrometry confirmed that the metabolites corresponded to the compounds of Example 3. Therefore, the metabolites described for the compounds of each Example herein refer to the compounds of Example 3.

[0540] For compounds of Formula I that retain free hydroxyl groups, such as the compounds of Examples 3 and 8, certain concentrations of the compounds can be detected in the serum and brain up to 72 hours after administration (Figures 1-8), indicating that such compounds have good blood-brain barrier permeability. For compounds of Formula I with further modified hydroxyl groups, such as the compounds of Examples 13, 21, 22, 26, and 28, lower concentrations of the compounds themselves and higher concentrations of metabolites can be detected in the serum and brain after administration, indicating that such compounds themselves have certain blood-brain barrier permeability and are also converted into more potent metabolites through metabolic processes in the body, thereby maintaining a certain drug concentration for a long time. For the compound of Example 15, no effective concentration of the compound itself was detected in the serum and brain, but a higher concentration of metabolites was detected, indicating that the compound may undergo metabolic processes quickly in the body, thereby being converted into metabolites to maintain a certain drug concentration.

[0541] It was also surprisingly found that although the compound of Example 24 was partially metabolized to the compound of Example 3 after administration, the total concentration of the original drug and metabolites in the brain after administration of the compound of Example 24 was significantly increased compared to the concentration in the brain after administration of the compound of Example 3 alone, as shown in Figure 27. Furthermore, the bioavailability of the compounds of Example 24 and Example 3 in the brain after administration was compared, as shown in Table 3 below:

[0542] Table 3. Comparison of AUC in mouse brain after administration of Example 3 and Example 24

[0543] As can be seen from the results in the above table, compared with the compound of Example 3, the bioavailability of the compound of Example 24 in the brain is significantly improved after administration.

[0544] In summary, the above biological activity tests demonstrate that the novel aromatic propionamide ester compounds designed in the present invention meet the basic requirements of neuroactive androgen receptor modulators and are a class of full androgen receptor agonists that can penetrate the blood-brain barrier.

[0545] The present invention has been described through the above embodiments, but it should be understood that the above embodiments are for illustrative and illustrative purposes only and are not intended to limit the present invention to the scope of the described embodiments. Those skilled in the art will also understand that the present invention is not limited to the above embodiments and that various variations and modifications may be made based on the teachings of the present invention, all of which fall within the scope of the present invention. The scope of protection of the present invention is defined by the appended claims and their equivalents.

Claims

1. Compounds of formula I: or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopic derivative thereof, wherein R 1 and R 2 are independently cyano, halogen, halogenated C 1 -C 6 Alkyl, nitro or -NR 5 R 6 ; R 3 and R 4 are independently hydrogen, cyano, halogen, halogenated C 1 -C 6 Alkyl, nitro, -NR 5 R 6 、-C(O)C 1 -C 6 Alkyl, -N(R 7 )C(O)C 1 -C 6 Alkyl, -N(R 7 )C(O)-halogenated C 1 -C 6 Alkyl, -C 1 -C 6 Alkyl C(O)C 1 -C 6 Alkyl, -S(O) 2 -C 1 -C 6 Alkyl, -N(R 7 )-S(O) 2 -C 1 -C 6 Alkyl, C 1 -C 6 Alkyl or C 1 -C 6 Alkoxy; W is CH or N; L is a bond, -C(O)-, -C(O)O-, -S(O) 2 - or -C(O)NH-; R is hydrogen, C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl, C 6 -C 10 Aryl, 3- to 12-membered heterocyclyl, 3- to 12-membered heterocyclyl-C 1 -C 6 alkyl, 5- to 12-membered heteroaryl, -C 1 -C 6 Alkyl-NR 5 R 6 , glucosyl and amino acids, wherein the heterocyclic and heteroaryl groups contain 1 or 2 heteroatoms independently selected from N, O or S, and the cycloalkyl, aryl, heterocyclic and heteroaryl groups are optionally substituted by 1 or 2 heteroatoms independently selected from C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen, cyano substituents; and R 5 , R 6 and R 7 Each independently is H or C 1 -C 6 alkyl.

2. The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopic derivative thereof, wherein the compound has the following formula II: Where R 1 , R 2 , R 3 , R 4 and W as defined in claim 1.

3. The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopic derivative thereof, wherein the compound has the following formula III: Where R 1 , R 2 , R 3 , R 4 , W and R are as defined in claim 1, with the proviso that R is not hydrogen.

4. The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopic derivative thereof, wherein the compound has the following formula IV: Where R 1 , R 2 , R 3 , R 4 , W and R are as defined in claim 1, with the proviso that R is not hydrogen.

5. The compound according to any one of claims 1 and 3-4, or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopic derivative thereof, wherein R is C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl, C 6 -C 10 Aryl, 4- to 7-membered heterocyclyl, 4- to 7-membered heterocyclyl-C 1 -C 6 alkyl, 5- to 10-membered heteroaryl or -C 1 -C 6 Alkyl-NR 5 R 6 wherein the cycloalkyl, aryl, heterocyclyl and heteroaryl are optionally substituted by 1 or 2 independently selected from C 1 -C 6 Alkyl, C 1 -C 6 The substituents are substituted by alkoxy, halogen, or cyano.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopic derivative thereof, wherein R 1 and R 2 are each independently cyano, halogen, trifluoromethyl, difluoromethyl, nitro or -NH 2 .

7. The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopic derivative thereof, wherein R 3 For cyano, halogen, halogenated C 1 -C 6 Alkyl, nitro, -NH 2 、-C(O)C 1 -C 6 Alkyl, -NHC(O)C 1 -C 6 Alkyl, -NHC(O)-halogenated C 1 -C 6 Alkyl, -S(O) 2 -C 1 -C 6 Alkyl or -NH-S(O) 2 -C 1 -C 6 alkyl.

8. The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopic derivative thereof, wherein R 4 is hydrogen or halogen.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopic derivative thereof, wherein R 1 is trifluoromethyl or halogen, and R 2 It is cyano.

10. The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopic derivative thereof, wherein R 3 is cyano or halogen, and R 4 is hydrogen or halogen.

11. The compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopic derivative thereof, in: R 1 and R 2 are each independently cyano, halogen, trifluoromethyl, difluoromethyl, nitro or -NH 2 ; R 3 For cyano, halogen, halogenated C 1 -C 6 Alkyl, nitro, -C(O)C 1 -C 6 Alkyl, -NHC(O)C 1 -C 6 Alkyl, -NHC(O)-halogenated C 1 -C 6 Alkyl, -S(O) 2 -C 1 -C 6 Alkyl or -NH-S(O) 2 -C 1 -C 6 alkyl; R 4 is hydrogen or halogen; W is CH or N; L is a bond, -C(O)- or -S(O) 2 -; R is hydrogen, C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl, C 6 -C 10 Aryl, 4- to 7-membered heterocyclyl, 4- to 7-membered heterocyclyl-C 1 -C 6 alkyl, 5- to 10-membered heteroaryl or -C 1 -C 6 Alkyl-NR 5 R 6 wherein the heterocyclic group and the heteroaryl group contain 1 or 2 heteroatoms independently selected from N, O or S, and the cycloalkyl, aryl, heterocyclic group and heteroaryl group are optionally substituted by 1 or 2 heteroatoms selected from C 1 -C 6 The alkyl group is substituted with a substituent; and R 5 and R 6 Each independently is H or C 1 -C 6 alkyl.

12. The compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopic derivative thereof, in: R 1 is trifluoromethyl or halogen; R 2 is cyano; R 3 is cyano or halogen; R 4 is hydrogen or halogen; W is CH or N; L is a bond, -C(O)- or -S(O) 2 -; R is hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopentyl, phenyl, piperidinyl optionally substituted by methyl, pyrrolidinyl optionally substituted by methyl, dihydropyridinyl optionally substituted by methyl, pyridinyl, dimethylaminoethyl and 13. A compound or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopic derivative thereof, wherein the compound is selected from:

14. A pharmaceutical composition comprising the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt, stereoisomer, solvate or isotopic derivative thereof and one or more pharmaceutically acceptable carriers.

15. Use of the compound according to any one of claims 1 to 13 or its pharmaceutically acceptable salt, stereoisomer, solvate or isotope derivative or the pharmaceutical composition according to claim 14 in the preparation of a medicament for preventing and / or treating androgen-related diseases.

16. The method of claim 15, wherein the disease is a central nervous system disease selected from dementia (including Alzheimer's disease), cognitive deficits in schizophrenia, Parkinson's disease, Huntington's disease, depression, anxiety, stroke, cerebral ischemia, amyotrophic lateral sclerosis, traumatic brain injury, fragile X syndrome, Rett syndrome, brain tumors and obesity.

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